Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 2 (ASPP2); ASPP2, also termed Bcl2-binding protein (Bbp), or renal carcinoma antigen NY-REN-51, or tumor suppressor p53-binding protein 2 (53BP2), or p53-binding protein 2 (p53BP2), is a member of ASPP protein family and it functions as a tumor suppressor. ASPP2 binds to p53 and enhances p53-mediated transcription of proapoptotic genes. ASSP2 contains a RA domain at the N-terminus. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumor suppression to being oncoproteins. All p53 amino acids that are important for ASPP2 binding are mutated in human cancer, and ASPP2 is frequently downregulated in these tumor cells.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611   10 MFLTVYLSNSEQHFTEVPVTPETVCRDVVDLCKEPGESDCHLAEVWCGSERPVADNERMFDVLQRFGSQRNEVRFFLRHE 89
Cdd:cd17225      1 MFLTVYLSNNEQHFTEVPITPETTCRDVVELCKEPGETDCHLAEVWRGSERPVADNERMLDVLQQWGAQRNEVRFFLRHE 80

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  935 DPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQVCKFLVESGAAVFAMTYSDMqTAA 1014
Cdd:COG0666    145 DVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGK-TAL 223

                   .
gi 1958674611 1015 D 1015
Cdd:COG0666    224 D 224

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  129 RLDLTLAELQEMASRQQQQIEAQQQMLATKEQRLKFLKQQDQRQQQqaaeqeKLKRLREIAESQEAKLKKVRALKGHVEQ 208
Cdd:TIGR02168  299 RLEQQKQILRERLANLERQLEELEAQLEELESKLDELAEELAELEE------KLEELKEELESLEAELEELEAELEELES 372

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  209 KrlsNGKLVEEIEQMNSLFQQKQRELVLAVSKVEELTRQLEmlkngRIDGHHDNQSavAELDRLYKELQLRNKlnQEQNA 288
Cdd:TIGR02168  373 R---LEELEEQLETLRSKVAQLELQIASLNNEIERLEARLE-----RLEDRRERLQ--QEIEELLKKLEEAEL--KELQA 440

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|..
gi 1958674611  289 KLQQQRECLNKRNSEVAVMDKRVNELRDRLWKKKAALQQKEN 330
Cdd:TIGR02168  441 ELEELEEELEELQEELERLEEALEELREELEEAEQALDAAER 482

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 2 (ASPP2); ASPP2, also termed Bcl2-binding protein (Bbp), or renal carcinoma antigen NY-REN-51, or tumor suppressor p53-binding protein 2 (53BP2), or p53-binding protein 2 (p53BP2), is a member of ASPP protein family and it functions as a tumor suppressor. ASPP2 binds to p53 and enhances p53-mediated transcription of proapoptotic genes. ASSP2 contains a RA domain at the N-terminus. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumor suppression to being oncoproteins. All p53 amino acids that are important for ASPP2 binding are mutated in human cancer, and ASPP2 is frequently downregulated in these tumor cells.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611   10 MFLTVYLSNSEQHFTEVPVTPETVCRDVVDLCKEPGESDCHLAEVWCGSERPVADNERMFDVLQRFGSQRNEVRFFLRHE 89
Cdd:cd17225      1 MFLTVYLSNNEQHFTEVPITPETTCRDVVELCKEPGETDCHLAEVWRGSERPVADNERMLDVLQQWGAQRNEVRFFLRHE 80

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  935 DPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQVCKFLVESGAAVFAMTYSDMqTAA 1014
Cdd:COG0666    145 DVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGK-TAL 223

                   .
gi 1958674611 1015 D 1015
Cdd:COG0666    224 D 224

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|
gi 1958674611  1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLND-KEGYVPRN 1096
Cdd:smart00326    7 ALYDYTAQDPDELSFKKGDIITVLEKSDDG---WWKGRLGRgKEGLFPSN 53

ankyrin repeat protein; Provisional

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1958674611  935 DPSLPNDEGITALHNAV--CAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCN--NVQVCKFLVESGAAVFAMT 1006
Cdd:PHA03100    98 NVNAPDNNGITPLLYAIskKSNSYSIVEYLLDNGANVNIKNSDGENLLHLYLESNkiDLKILKLLIDKGVDINAKN 173

chromosome segregation protein SMC, common bacterial type; SMC (structural maintenance of chromosomes) proteins bind DNA and act in organizing and segregating chromosomes for partition. SMC proteins are found in bacteria, archaea, and eukaryotes. This family represents the SMC protein of most bacteria. The smc gene is often associated with scpB (TIGR00281) and scpA genes, where scp stands for segregation and condensation protein. SMC was shown (in Caulobacter crescentus) to be induced early in S phase but present and bound to DNA throughout the cell cycle. [Cellular processes, Cell division, DNA metabolism, Chromosome-associated proteins]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  129 RLDLTLAELQEMASRQQQQIEAQQQMLATKEQRLKFLKQQDQRQQQqaaeqeKLKRLREIAESQEAKLKKVRALKGHVEQ 208
Cdd:TIGR02168  299 RLEQQKQILRERLANLERQLEELEAQLEELESKLDELAEELAELEE------KLEELKEELESLEAELEELEAELEELES 372

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  209 KrlsNGKLVEEIEQMNSLFQQKQRELVLAVSKVEELTRQLEmlkngRIDGHHDNQSavAELDRLYKELQLRNKlnQEQNA 288
Cdd:TIGR02168  373 R---LEELEEQLETLRSKVAQLELQIASLNNEIERLEARLE-----RLEDRRERLQ--QEIEELLKKLEEAEL--KELQA 440

                          170       180       190       200
                   ....*....|....*....|....*....|....*....|..
gi 1958674611  289 KLQQQRECLNKRNSEVAVMDKRVNELRDRLWKKKAALQQKEN 330
Cdd:TIGR02168  441 ELEELEEELEELQEELERLEEALEELREELEEAEQALDAAER 482

Uncharacterized protein, contains DUF3084 domain [Function unknown];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  206 VEQKRLSNGKLVEEIEQMNSLFQQKQRElvlAVSKVEELTRQLEMLKNgridghhDNQSAVAELDRLYKELQLRNKLNQE 285
Cdd:COG4372      8 VGKARLSLFGLRPKTGILIAALSEQLRK---ALFELDKLQEELEQLRE-------ELEQAREELEQLEEELEQARSELEQ 77

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|..
gi 1958674611  286 QNAKLQQQRECLNKRNSEVAVMDKRVNELRDRLWKKKAALQQ 327
Cdd:COG4372     78 LEEELEELNEQLQAAQAELAQAQEELESLQEEAEELQEELEE 119

DNA double-strand break repair ATPase Rad50;

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  154 MLATKEQRLKFLKQQDQRQQQQAAEQEKLKRLREIAESQEAKLKKVRALKGHVEQKRLSNGKLVEEIEQMNSlfqqKQRE 233
Cdd:PRK03918   267 RIEELKKEIEELEEKVKELKELKEKAEEYIKLSEFYEEYLDELREIEKRLSRLEEEINGIEERIKELEEKEE----RLEE 342

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  234 LvlaVSKVEELTRQLEMLKnGRIDGHHDNQSAVAELDRLYKEL------QLRNKLNQEQNAKLQQQREcLNKRNSEVAVM 307
Cdd:PRK03918   343 L---KKKLKELEKRLEELE-ERHELYEEAKAKKEELERLKKRLtgltpeKLEKELEELEKAKEEIEEE-ISKITARIGEL 417

                          170
                   ....*....|....*..
gi 1958674611  308 DKRVNELRDRLWKKKAA 324
Cdd:PRK03918   418 KKEIKELKKAIEELKKA 434

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 2 (ASPP2); ASPP2, also termed Bcl2-binding protein (Bbp), or renal carcinoma antigen NY-REN-51, or tumor suppressor p53-binding protein 2 (53BP2), or p53-binding protein 2 (p53BP2), is a member of ASPP protein family and it functions as a tumor suppressor. ASPP2 binds to p53 and enhances p53-mediated transcription of proapoptotic genes. ASSP2 contains a RA domain at the N-terminus. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumor suppression to being oncoproteins. All p53 amino acids that are important for ASPP2 binding are mutated in human cancer, and ASPP2 is frequently downregulated in these tumor cells.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611   10 MFLTVYLSNSEQHFTEVPVTPETVCRDVVDLCKEPGESDCHLAEVWCGSERPVADNERMFDVLQRFGSQRNEVRFFLRHE 89
Cdd:cd17225      1 MFLTVYLSNNEQHFTEVPITPETTCRDVVELCKEPGETDCHLAEVWRGSERPVADNERMLDVLQQWGAQRNEVRFFLRHE 80

Ras-associating (RA) domain found in apoptosis-stimulating protein of p53 protein 1 (ASPP1); ASPP1 is a member of the ASPP protein family (Apoptosi-Stimulating Protein of p53) that activates the p53-mediated apoptotic response. ASSP1 functions as a tumor suppressor and coordinates with p53 to protect hematopoietic stem cell (HSC) pool integrity, guarding against hematological malignancies. ASSP1 contains a RA domain at the N-terminus. The RA domain is a ubiquitin-like domain and RA domain-containing proteins are involved in several different functions ranging from tumor suppression to being oncoproteins.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611    8 MPMFLTVYLSNSEQHFTEVPVTPETVCRDVVDLCKEPGESDCHLAEVWCGSERPVADNERMFDVLQRFGSQRNEVRFFLR 87
Cdd:cd17224      1 MPMILTVFLSNNEQILTEVPITPETTCRDVVEFCKEPGETGCHLAEVWRGNERPIPYDHMMYEHLQKWGPRREEVKFFLR 80

                   ....*
gi 1958674611   88 HERPP 92
Cdd:cd17224     81 HEDSP 85

Src homology 3 domain of Apoptosis Stimulating of p53 proteins (ASPP); The ASPP family of proteins bind to important regulators of apoptosis (p53, Bcl-2, and RelA) and cell growth (APCL, PP1). They share similarity at their C-termini, where they harbor a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain. Vertebrates contain three members of the family: ASPP1, ASPP2, and iASPP. ASPP1 and ASPP2 activate the apoptotic function of the p53 family of tumor suppressors (p53, p63, and p73), while iASPP is an oncoprotein that specifically inhibits p53-induced apoptosis. The expression of ASPP proteins is altered in tumors; ASPP1 and ASPP2 are downregulated whereas iASPP is upregulated is some cancer types. ASPP proteins also bind and regulate protein phosphatase 1 (PP1), and this binding is competitive with p53 binding. The SH3 domain and the ANK repeats of ASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*..
gi 1958674611 1044 GVIYALWDYQPQHDDELLLKEGDCMAVVRREDEDETEWWWARLNDKEGYVPRNLLGL 1100
Cdd:cd11807      1 GVVYALFDYEAENGDELSFREGDELTVLRKGDDDETEWWWARLNDKEGYVPRNLLGL 57

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  935 DPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQVCKFLVESGAAVFAMTYSDMqTAA 1014
Cdd:COG0666    145 DVNAQDNDGNTPLHLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENGHLEIVKLLLEAGADVNAKDNDGK-TAL 223

                   .
gi 1958674611 1015 D 1015
Cdd:COG0666    224 D 224

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  912 ALLLDSSLEGEFDLVQRIIYEVDDPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQV 991
Cdd:COG0666     89 TLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPLHLAAANGNLEI 168

                           90
                   ....*....|.
gi 1958674611  992 CKFLVESGAAV 1002
Cdd:COG0666    169 VKLLLEAGADV 179

Ankyrin repeat [Signal transduction mechanisms];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  909 NPLALLLDSSLEGEFDLVQRIIYEVDDPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNN 988
Cdd:COG0666     53 LGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAARNGDLEIVKLLLEAGADVNARDKDGETPLHLAAYNGN 132

                           90
                   ....*....|....
gi 1958674611  989 VQVCKFLVESGAAV 1002
Cdd:COG0666    133 LEIVKLLLEAGADV 146

Ankyrin repeats (many copies);

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1958674611  945 TALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAASCNNVQVCKFLV 996
Cdd:pfam13637    3 TALHAAAASGHLELLRLLLEKGADINAVDGNGETALHFAASNGNVEVLKLLL 54

Src Homology 3 domain superfamily; Src Homology 3 (SH3) domains are protein interaction domains that bind proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. Thus, they are referred to as proline-recognition domains (PRDs). SH3 domains are less selective and show more diverse specificity compared to other PRDs. They have been shown to bind peptide sequences that lack the PxxP motif; examples include the PxxDY motif of Eps8 and the RKxxYxxY sequence in SKAP55. SH3 domain containing proteins play versatile and diverse roles in the cell, including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies, among others. Many members of this superfamily are adaptor proteins that associate with a number of protein partners, facilitating complex formation and signal transduction.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLND-KEGYVPRN 1096
Cdd:cd00174      4 ALYDYEAQDDDELSFKKGDIITVLEKDDDG---WWEGELNGgREGLFPAN 50

Src homology 3 domains; Src homology 3 (SH3) domains bind to target proteins through sequences containing proline and hydrophobic amino acids. Pro-containing polypeptides may bind to SH3 domains in 2 different binding orientations.

                            10        20        30        40        50
                    ....*....|....*....|....*....|....*....|....*....|
gi 1958674611  1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLND-KEGYVPRN 1096
Cdd:smart00326    7 ALYDYTAQDPDELSFKKGDIITVLEKSDDG---WWKGRLGRgKEGLFPSN 53

Src homology 3 domain of Brk (Breast tumor kinase) Protein Tyrosine Kinase (PTK), also called PTK6; Brk is a cytoplasmic (or non-receptor) PTK with limited homology to Src kinases. It has been found to be overexpressed in a majority of breast tumors. It plays roles in normal cell differentiation, proliferation, survival, migration, and cell cycle progression. Brk substrates include RNA-binding proteins (SLM-1/2, Sam68), transcription factors (STAT3/5), and signaling molecules (Akt, paxillin, IRS-4). Src kinases in general contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr; they are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). However, Brk lacks the N-terminal myristoylation site. The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611 1046 IY-ALWDYQPQHDDELLLKEGDCMAVVRREDedetEWWWARLNDK------EGYVPRNLL 1098
Cdd:cd11847      1 IYkALWDFKARGDEELSFQAGDQFRIAERSG----DWWTALKLDRaggvvaQGFVPNNYL 56

Third Src Homology 3 domain (SH3C) of CD2-associated protein and similar proteins; This subfamily is composed of the third SH3 domain (SH3C) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3C of both proteins have been shown to bind to ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDETeWWWARLNDKEGYVPRN 1096
Cdd:cd11875      4 VLFDYEAENEDELTLREGDIVTILSKDCEDKG-WWKGELNGKRGVFPDN 51

Src homology 3 domains of the p47phox subunit of NADPH oxidase and similar domains; This family is composed of the tandem SH3 domains of p47phox subunit of NADPH oxidase and Nox Organizing protein 1 (NoxO1), the four SH3 domains of Tks4 (Tyr kinase substrate with four SH3 domains), the five SH3 domains of Tks5, the SH3 domain of obscurin, Myosin-I, and similar domains. Most members of this group also contain Phox homology (PX) domains, except for obscurin and Myosin-I. p47phox and NoxO1 are regulators of the phagocytic NADPH oxidase complex (also called Nox2 or gp91phox) and nonphagocytic NADPH oxidase Nox1, respectively. They play roles in the activation of their respective NADPH oxidase, which catalyzes the transfer of electrons from NADPH to molecular oxygen to form superoxide. Tks proteins are Src substrates and scaffolding proteins that play important roles in the formation of podosomes and invadopodia, the dynamic actin-rich structures that are related to cell migration and cancer cell invasion. Obscurin is a giant muscle protein that plays important roles in the organization and assembly of the myofibril and the sarcoplasmic reticulum. Type I myosins (Myosin-I) are actin-dependent motors in endocytic actin structures and actin patches. They play roles in membrane traffic in endocytic and secretory pathways, cell motility, and mechanosensing. Myosin-I contains an N-terminal actin-activated ATPase, a phospholipid-binding TH1 (tail homology 1) domain, and a C-terminal extension which includes an F-actin-binding TH2 domain, an SH3 domain, and an acidic peptide that participates in activating the Arp2/3complex. The SH3 domain of myosin-I is required for myosin-I-induced actin polymerization. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1958674611 1047 YALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVPRNLL 1098
Cdd:cd11856      3 VAIADYEAQGDDEISLQEGEVVEVLEKNDSG---WWYVRKGDKEGWVPASYL 51

Second C-terminal Src homology 3 domain of Dynamin Binding Protein, also called Tuba, and similar domains; DNMBP or Tuba is a cdc42-specific guanine nucleotide exchange factor (GEF) that contains four N-terminal SH3 domains, a central RhoGEF [or Dbl homology (DH)] domain followed by a Bin/Amphiphysin/Rvs (BAR) domain, and two C-terminal SH3 domains. It provides a functional link between dynamin, Rho GTPase signaling, and actin dynamics. It plays an important role in regulating cell junction configuration. The C-terminal SH3 domains of DNMBP bind to N-WASP and Ena/VASP proteins, which are key regulatory proteins of the actin cytoskeleton. Also included in this subfamily is the second C-terminal SH3 domain of Rho guanine nucleotide exchange factor 37 (ARHGEF37), whose function is still unknown. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....*.
gi 1958674611 1045 VIYALWDYQPQHDDELLLKEGDCMAVVRRED-EDETEWWWARLNDKEGYVPRNLLG 1099
Cdd:cd11800      1 YYYALYTFEARSPGELSVTEGQVVTVLEKHDlKGNPEWWLVEDRGKQGYVPSNYLA 56

Src homology 3 domain of APC-Stimulated guanine nucleotide Exchange Factor 2; ASEF2, also called Spermatogenesis-associated protein 13 (SPATA13), is a GEF that localizes with actin at the leading edge of cells and is important in cell migration and adhesion dynamics. GEFs activate small GTPases by exchanging bound GDP for free GTP. ASEF2 can activate both Rac 1 and Cdc42, but only Rac1 activation is necessary for increased cell migration and adhesion turnover. Together with APC (adenomatous polyposis coli) and Neurabin2, a scaffold protein that binds F-actin, it is involved in regulating HGF-induced cell migration. ASEF2 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDcmaVVRREDEDETEWWWARLNDKEGYVPRNLLGL 1100
Cdd:cd11974      5 ALWDHVTMDDQELAFKAGD---VIRVLEASNKDWWWGRNEDREAWFPASFVRL 54

Second Src Homology 3 domain (SH3B) of CD2-associated protein and similar proteins; This subfamily is composed of the second SH3 domain (SH3B) of CD2AP, CIN85 (Cbl-interacting protein of 85 kDa), and similar domains. CD2AP and CIN85 are adaptor proteins that bind to protein partners and assemble complexes that have been implicated in T cell activation, kidney function, and apoptosis of neuronal cells. They also associate with endocytic proteins, actin cytoskeleton components, and other adaptor proteins involved in receptor tyrosine kinase (RTK) signaling. CD2AP and the main isoform of CIN85 contain three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CD2AP and CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. SH3B of both proteins have been shown to bind to Cbl. In the case of CD2AP, its SH3B binds to Cbl at a site distinct from the c-Cbl/SH3A binding site. The CIN85 SH3B also binds ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVrreDEDETEWWWARLNDKEGYVPRN 1096
Cdd:cd11874      4 VLFSYTPQNEDELELKVGDTIEVL---GEVEEGWWEGKLNGKVGVFPSN 49

Src homology 3 domain of ARHGEF9-like Rho guanine nucleotide exchange factors; Members of this family contain a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. They include the Rho guanine nucleotide exchange factors ARHGEF9, ASEF (also called ARHGEF4), ASEF2, and similar proteins. GEFs activate small GTPases by exchanging bound GDP for free GTP. ARHGEF9 specifically activates Cdc42, while both ASEF and ASEF2 can activate Rac1 and Cdc42. ARHGEF9 is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. ASEF plays a role in angiogenesis and cell migration. ASEF2 is important in cell migration and adhesion dynamics. ASEF exists in an autoinhibited form and is activated upon binding of the tumor suppressor APC (adenomatous polyposis coli), leading to the activation of Rac1 or Cdc42. In its autoinhibited form, the SH3 domain of ASEF forms an extensive interface with the DH and PH domains, blocking the Rac binding site. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVP 1094
Cdd:cd11828      4 ALWDHVTMDPEELGFKAGDVIEVLDMSDKD---WWWGSIRDEEGWFP 47

Src homology 3 domain of Nitric Oxide Synthase TRaffic INducer; Nostrin is expressed in endothelial and epithelial cells and is involved in the regulation, trafficking and targeting of endothelial NOS (eNOS). It facilitates the endocytosis of eNOS by coordinating the functions of dynamin and the Wiskott-Aldrich syndrome protein (WASP). Increased expression of Nostrin may be correlated to preeclampsia. Nostrin contains an N-terminal F-BAR domain and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVPRN 1096
Cdd:cd11823      4 ALYSYTANREDELSLQPGDIIEVHEKQDDG---WWLGELNGKKGIFPAT 49

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2 (GRB2) and related proteins; This family includes the adaptor protein GRB2 and related proteins including Drosophila melanogaster Downstream of receptor kinase (DRK), Caenorhabditis elegans Sex muscle abnormal protein 5 (Sem-5), GRB2-related adaptor protein (GRAP), GRAP2, and similar proteins. Family members contain an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. GRB2/Sem-5/DRK is a critical signaling molecule that regulates the Ras pathway by linking tyrosine kinases to the Ras guanine nucleotide releasing protein Sos (son of sevenless), which converts Ras to the active GTP-bound state. GRAP2 plays an important role in T cell receptor (TCR) signaling by promoting the formation of the SLP-76:LAT complex, which couples the TCR to the Ras pathway. GRAP acts as a negative regulator of T cell receptor (TCR)-induced lymphocyte proliferation by downregulating the signaling to the Ras/ERK pathway. The C-terminal SH3 domains (SH3c) of GRB2 and GRAP2 have been shown to bind to classical PxxP motif ligands, as well as to non-classical motifs. GRB2 SH3c binds Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, while the SH3c of GRAP2 binds to the phosphatase-like protein HD-PTP via a RxxxxK motif. SH3 domains are protein interaction domains that typically bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVPRN 1096
Cdd:cd11805      4 ALYDFNPQEPGELEFRRGDIITVLDSSDPD---WWKGELRGRVGIFPAN 49

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  332 PVSPDGNPPQQAVSAPSRVAAVGPY-MQSSTMPRMPSRPELLGKPALPDSSLVMQSAEGPMKiqtlpnMRSGAASQSKGP 410
Cdd:PHA03247  2601 PVDDRGDPRGPAPPSPLPPDTHAPDpPPPSPSPAANEPDPHPPPTVPPPERPRDDPAPGRVS------RPRRARRLGRAA 2674

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  411 KAHSASSDWNPSStdLLPSQGSGSAL----DQVDEGEIALREKEKKVrPFSMFDTVDQCAPPPSFGTLRKNQSSEDILRD 486
Cdd:PHA03247  2675 QASSPPQRPRRRA--ARPTVGSLTSLadppPPPPTPEPAPHALVSAT-PLPPGPAAARQASPALPAAPAPPAVPAGPATP 2751

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  487 AQPKQINLPYFGQTAQSSSD--VKPDGNPQQLPIAATSMGAKLKPAGPQARVLLSPSAPSGGQDQVLSPASkqeSPPAAA 564
Cdd:PHA03247  2752 GGPARPARPPTTAGPPAPAPpaAPAAGPPRRLTRPAVASLSESRESLPSPWDPADPPAAVLAPAAALPPAA---SPAGPL 2828

                          250       260       270       280       290       300       310       320
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  565 VRPFTPQPSKDTFPPAFRKPQTVAASSIysmytqhqVPGKNF------QQAVQSASTKTHPRGPHFSS-VYGKPVIAAAQ 637
Cdd:PHA03247  2829 PPPTSAQPTAPPPPPGPPPPSLPLGGSV--------APGGDVrrrppsRSPAAKPAAPARPPVRRLARpAVSRSTESFAL 2900

                          330       340       350       360       370       380       390       400
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  638 NPQQHPENIYSCSQGKPGSPEPETEPVSSVHESHENERIPRPLSPTKLLPFLSNPYRNQSDADLEALRKKLSNAPRPL-- 715
Cdd:PHA03247  2901 PPDQPERPPQPQAPPPPQPQPQPPPPPQPQPPPPPPPRPQPPLAPTTDPAGAGEPSGAVPQPWLGALVPGRVAVPRFRvp 2980

                          410
                   ....*....|....*.
gi 1958674611  716 KKRSSITEPEGPNGPN 731
Cdd:PHA03247  2981 QPAPSREAPASSTPPL 2996

Fourth Src homology 3 domain of ADAM-binding protein Eve-1; Eve-1, also called SH3 domain-containing protein 19 (SH3D19) or EEN-binding protein (EBP), exists in multiple alternatively spliced isoforms. The longest isoform contains five SH3 domain in the C-terminal region and seven proline-rich motifs in the N-terminal region. It is abundantly expressed in skeletal muscle and heart, and may be involved in regulating the activity of ADAMs (A disintegrin and metalloproteases). Eve-1 interacts with EEN, an endophilin involved in endocytosis and may be the target of the MLL-EEN fusion protein that is implicated in leukemogenesis. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDedeTEWWWARLNDKEGYVPRN 1096
Cdd:cd11817      4 ALYDFTGETEEDLSFQRGDRILVTEHLD---AEWSRGRLNGREGIFPRA 49

Src Homology 3 domain of Src Kinase-Associated Phosphoprotein 1 and similar proteins; This subfamily is composed of SKAP1, SKAP2, and similar proteins. SKAP1 and SKAP2 are immune cell-specific adaptor proteins that play roles in T- and B-cell adhesion, respectively, and are thus important in the migration of T- and B-cells to sites of inflammation and for movement during T-cell conjugation with antigen-presenting cells. Both SKAP1 and SKAP2 bind to ADAP (adhesion and degranulation-promoting adaptor protein), among many other binding partners. They contain a pleckstrin homology (PH) domain, a C-terminal SH3 domain, and several tyrosine phosphorylation sites. The SH3 domain of SKAP1 is necessary for its ability to regulate T-cell conjugation with antigen-presenting cells and the formation of LFA-1 clusters. SKAP1 binds primarily to a proline-rich region of ADAP through its SH3 domain; its degradation is regulated by ADAP. A secondary interaction occurs via the ADAP SH3 domain and the RKxxYxxY motif in SKAP1. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREdEDETEWWWARLNDKEGYVPRNLL 1098
Cdd:cd11866      4 GLWDCSGNEPDELSFKRGDLIYIISKE-YDSFGWWVGELNGKVGLVPKDYL 53

Src homology 3 domain of Endophilin-A; Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition, and endosomal sorting. They are classified into two types, A and B. Vertebrates contain three endophilin-A isoforms (A1, A2, and A3). Endophilin-A proteins are enriched in the brain and play multiple roles in receptor-mediated endocytosis. They tubulate membranes and regulate calcium influx into neurons to trigger the activation of the endocytic machinery. They are also involved in the sorting of plasma membrane proteins, actin filament assembly, and the uncoating of clathrin-coated vesicles for fusion with endosomes. Endophilins contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVPRN 1096
Cdd:cd11803      5 ALYDFEPENEGELGFKEGDIITLTNQIDEN---WYEGMVNGQSGFFPVN 50

Second Src Homology 3 domain (SH3B) of Cbl-interacting protein of 85 kDa; CIN85, also called SH3 domain-containing kinase-binding protein 1 (SH3KBP1) or CD2-binding protein 3 (CD2BP3) or Ruk, is an adaptor protein that is involved in the downregulation of receptor tyrosine kinases by facilitating endocytosis through interaction with endophilin-associated ubiquitin ligase Cbl proteins. It is also important in many other cellular processes including vesicle-mediated transport, cytoskeletal remodelling, apoptosis, cell adhesion and migration, and viral infection, among others. CIN85 exists as multiple variants from alternative splicing; the main variant contains three SH3 domains, a proline-rich region, and a C-terminal coiled-coil domain. All of these domains enable CIN85 to bind various protein partners and assemble complexes that have been implicated in many different functions. This alignment model represents the second SH3 domain (SH3B) of CIN85. SH3B has been shown to bind Cbl proline-rich peptides and ubiquitin. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVrreDEDETEWWWARLNDKEGYVPRNLL 1098
Cdd:cd12055      4 VAFSYLPQNEDELELKVGDIIEVV---GEVEEGWWEGVLNGKTGMFPSNFI 51

ankyrin repeat protein; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958674611  922 EFDLVQRIIYEVDDPSLPNDEGITALHNAVCAGHTEIVKFLVQFGVNVNAADSDGWTPLHCAAS-CNNVQVCKFLVESGA 1000
Cdd:PHA02878   180 DQRLTELLLSYGANVNIPDKTNNSPLHHAVKHYNKPIVHILLENGASTDARDKCGNTPLHISVGyCKDYDILKLLLEHGV 259

                   ....*..
gi 1958674611 1001 AVFAMTY 1007
Cdd:PHA02878   260 DVNAKSY 266

Src homology 3 domain of the Rho guanine nucleotide exchange factor ARHGEF9; ARHGEF9, also called PEM2 or collybistin, selectively activates Cdc42 by exchanging bound GDP for free GTP. It is highly expressed in the brain and it interacts with gephyrin, a postsynaptic protein associated with GABA and glycine receptors. Mutations in the ARHGEF9 gene cause X-linked mental retardation with associated features like seizures, hyper-anxiety, aggressive behavior, and sensory hyperarousal. ARHGEF9 contains a SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVrreDEDETEWWWARLNDKEGYVPRNLLGLY 1101
Cdd:cd11975      9 AVWDHVTMANRELAFKAGDVIKVL---DASNKDWWWGQIDDEEGWFPASFVRLW 59

Src homology 3 domain of Protein arginine N-methyltransferase 2; PRMT2, also called HRMT1L1, belongs to the arginine methyltransferase protein family. It functions as a coactivator to both estrogen receptor alpha (ER-alpha) and androgen receptor (AR), presumably through arginine methylation. The ER-alpha transcription factor is involved in cell proliferation, differentiation, morphogenesis, and apoptosis, and is also implicated in the development and progression of breast cancer. PRMT2 and its variants are upregulated in breast cancer cells and may be involved in modulating the ER-alpha signaling pathway during formation of breast cancer. PRMT2 also plays a role in regulating the function of E2F transcription factors, which are critical cell cycle regulators, by binding to the retinoblastoma gene product (RB). It contains an N-terminal SH3 domain and an AdoMet binding domain. SH3 domains are protein interaction domains that bind to proline-rich ligands with moderate affinity and selectivity, preferentially to PxxP motifs. They play versatile and diverse roles in the cell including the regulation of enzymes, changing the subcellular localization of signaling pathway components, and mediating the formation of multiprotein complex assemblies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|..
gi 1958674611 1048 ALWDYQPQHDDELLLKEGDCMAVVRREDEDeteWWWARLNDKEGYVPRNLLG 1099
Cdd:cd11806      4 AIADFVATDDSQLSFESGDKLLVLRKPSVD---WWWAEHNGCCGYIPASHLH 52