FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 1 (SHANK1); SHANK1, also termed somatostatin receptor-interacting protein, or SSTR-interacting protein (SSTRIP), is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. Mutations in the SHANK1 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK1 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   70 FSMMVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYPQSFEKGV 149
Cdd:cd17175     1 FSMMVFRIGIPDLHQTKCLRFNPDATIWVAKQQVLCTLNESLKDVLNYGLFQPATNGRDAKFLEEERLLREYPQSFEKGV 80

                  ....*....
gi 768009462  150 PYLEFRYKT 158
Cdd:cd17175    81 PYLEFRYKT 89

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 768009462 2085 PLGFWTKFDVADWLEWLGLAEHRAQFLDHEIDGSHLPALTKEDYVDLGVTRVGHRMNIDRALKFFL 2150
Cdd:cd09506     1 PVHEWTVDDVGDWLESLNLGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERALKKLL 66

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 1; Shank1, also called SSTRIP (Somatostatin receptor-interacting protein), is a brain-specific protein that plays a role in the construction of postsynaptic density (PSD) and the maturation of dendritic spines. Mice deficient in Shank1 show altered PSD composition, thinner PSDs, smaller dendritic spines, and weaker basal synaptic transmission, although synaptic plasticity is normal. They show increased anxiety and impaired fear memory, but also show better spatial learning. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  557 RSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCL 608
Cdd:cd11982     1 RTFMAVKPYQSQAEGEISLSKGEKIKVLSVGEGGFWEGQVKGRVGWFPSDCV 52

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 1 (SHANK1); SHANK1, also termed somatostatin receptor-interacting protein, or SSTR-interacting protein (SSTRIP), is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. Mutations in the SHANK1 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK1 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   70 FSMMVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYPQSFEKGV 149
Cdd:cd17175     1 FSMMVFRIGIPDLHQTKCLRFNPDATIWVAKQQVLCTLNESLKDVLNYGLFQPATNGRDAKFLEEERLLREYPQSFEKGV 80

                  ....*....
gi 768009462  150 PYLEFRYKT 158
Cdd:cd17175    81 PYLEFRYKT 89

SAM domain of Shank1,2,3 family proteins; SAM (sterile alpha motif) domain of Shank1,2,3 family proteins is a protein-protein interaction domain. Shank1,2,3 proteins are scaffold proteins that are known to interact with a variety of cytoplasmic and membrane proteins. SAM domains of the Shank1,2,3 family are prone to homooligomerization. They are highly enriched in the postsynaptic density, acting as scaffolds to organize assembly of postsynaptic proteins. SAM domains of Shank3 proteins can form large sheets of helical fibers. Shank genes show distinct patterns of expression, in rat Shank1 mRNA is found almost exclusively in brain, Shank2 in brain, kidney and liver, and Shank3 in heart, brain and spleen.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 768009462 2085 PLGFWTKFDVADWLEWLGLAEHRAQFLDHEIDGSHLPALTKEDYVDLGVTRVGHRMNIDRALKFFL 2150
Cdd:cd09506     1 PVHEWTVDDVGDWLESLNLGEHRERFMDNEIDGSHLPNLDKEDLTELGVTRVGHRMNIERALKKLL 66

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 1; Shank1, also called SSTRIP (Somatostatin receptor-interacting protein), is a brain-specific protein that plays a role in the construction of postsynaptic density (PSD) and the maturation of dendritic spines. Mice deficient in Shank1 show altered PSD composition, thinner PSDs, smaller dendritic spines, and weaker basal synaptic transmission, although synaptic plasticity is normal. They show increased anxiety and impaired fear memory, but also show better spatial learning. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  557 RSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCL 608
Cdd:cd11982     1 RTFMAVKPYQSQAEGEISLSKGEKIKVLSVGEGGFWEGQVKGRVGWFPSDCV 52

ankyrin-like protein; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  174 LHT--KTGLKKFLEYVQLgtsdkvarLLDKGLDPNYHDSdSGETPLTLAAQTEGSVEVIRTLCLGGAHIDFRARDGMTAL 251
Cdd:PHA03095   51 LHLylHYSSEKVKDIVRL--------LLEAGADVNAPER-CGFTPLHLYLYNATTLDVIKLLIKAGADVNAKDKVGRTPL 121

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  252 HKaacarhCLA--------LTALLDLGGSPNYKDRRGLTPLfHTAMV--GGDPRCCELLLFNRAQLGIADENGWQEIHQA 321
Cdd:PHA03095  122 HV------YLSgfninpkvIRLLLRKGADVNALDLYGMTPL-AVLLKsrNANVELLRLLIDAGADVYAVDDRFRSLLHHH 194

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 768009462  322 CQ--RGHSQHLEHLLFYGAEPGAQNASGNTALHICALYNkeTCARI----LLYRGADKDVKNNNGQTPFQVAVIAGN 392
Cdd:PHA03095  195 LQsfKPRARIVRELIRAGCDPAATDMLGNTPLHSMATGS--SCKRSlvlpLLIAGISINARNRYGQTPLHYAAVFNN 269

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   318 IHQACQRGHSQHLEHLLFYGAEPGAQNASGNTALHICALYNKETCARILLyRGADKDVKnNNGQTPFQVAVIAGNFELGE 397
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLK-DNGRTALHYAARSGHLEIVK 78

                   ....*
gi 768009462   398 LIRNH 402
Cdd:pfam12796   79 LLLEK 83

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 768009462    555 PGRSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVK-GRVGWFPSDCLE 609
Cdd:smart00326    1 EGPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDGWWKGRLGrGKEGLFPSNYVE 56

Transient Receptor Potential channel, Vanilloid subfamily (TRPV), types 5 and 6; TRPV5 and TRPV6 (TRPV5/6) are two homologous members within the vanilloid subfamily of the transient receptor potential (TRP) family. TRPV5 and TRPV6 show only 30-40% homology with other members of the TRP family and have unique properties that differentiates them from other TRP channels. They mediate calcium uptake in epithelia and their expression is dramatically increased in numerous types of cancer. The structure of TRPV5/6 shows the typical topology features of all TRP family members, such as six transmembrane regions, a short hydrophobic stretch between transmembrane segments 5 and 6, which is predicted to form the Ca2+ pore, and large intracellular N- and C-terminal domains. The N-terminal domain of TRPV5/6 contains three ankyrin repeats. This structural element is present in several proteins and plays a role in protein-protein interactions. The N- and C-terminal tails of TRPV5/6 each contain an internal PDZ motif which can function as part of a molecular scaffold via interaction with PDZ-domain containing proteins. A major difference between the properties of TRPV5 and TRPV6 is in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues. In contrast, TRPV6 has a broader expression pattern such as expression in the intestine, kidney, placenta, epididymis, exocrine tissues, and a few other tissues.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  214 ETPLTLAAQtEGSVEVIRTLcLGGAHIDFRARDGM--TALHKAACARHCLALTALLDlgGSPN----------YKdrrGL 281
Cdd:cd22192    18 ESPLLLAAK-ENDVQAIKKL-LKCPSCDLFQRGALgeTALHVAALYDNLEAAVVLME--AAPElvnepmtsdlYQ---GE 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  282 TPLfHTAMV-------------GGD---PRCC---------ELLLFNRAQLGIAdengwqeihqACQrGHSQHLEHLLFY 336
Cdd:cd22192    91 TAL-HIAVVnqnlnlvreliarGADvvsPRATgtffrpgpkNLIYYGEHPLSFA----------ACV-GNEEIVRLLIEH 158

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 768009462  337 GAEPGAQNASGNTALHICALYNKETCAR-----ILLYRGADKD-----VKNNNGQTPFQVAVIAGNFELGE-LIRNHR 403
Cdd:cd22192   159 GADIRAQDSLGNTVLHILVLQPNKTFACqmydlILSYDKEDDLqpldlVPNNQGLTPFKLAAKEGNIVMFQhLVQKRR 236

N-terminal or F0 domain of Talin-head FERM; FERM_f0 forms a stable globular structure. The fold is an ubiquitin-like fold joined to the f1 domain in a novel fixed orientation by an extensive charged interface. It is required for maximal integrin-activation, by interacting with other FA components, No binding partner has yet been found for it.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 768009462    76 RIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYP 142
Cdd:pfam16511    4 KISIVGSNVTKTMQFDPSTTVYDACRLIREKIPEGGLNASEYGLFLADEDPKKGRWLEPGRTLEYYD 70

ankyrin repeats; Ankyrin repeats are about 33 amino acids long and occur in at least four consecutive copies. They are involved in protein-protein interactions. The core of the repeat seems to be an helix-loop-helix structure.

                            10        20
                    ....*....|....*....|....*....
gi 768009462    347 GNTALHICALYNKETCARILLYRGADKDV 375
Cdd:smart00248    2 GRTPLHLAAENGNLEVVKLLLDKGADINA 30

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 1 (SHANK1); SHANK1, also termed somatostatin receptor-interacting protein, or SSTR-interacting protein (SSTRIP), is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. Mutations in the SHANK1 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK1 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   70 FSMMVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYPQSFEKGV 149
Cdd:cd17175     1 FSMMVFRIGIPDLHQTKCLRFNPDATIWVAKQQVLCTLNESLKDVLNYGLFQPATNGRDAKFLEEERLLREYPQSFEKGV 80

                  ....*....
gi 768009462  150 PYLEFRYKT 158
Cdd:cd17175    81 PYLEFRYKT 89

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 2 (SHANK2); SHANK2, also termed cortactin-binding protein 1 (CortBP1), or proline-rich synapse-associated protein 1, is a postsynaptic density (PSD)-associated scaffolding proteins at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is strongly expressed in the cerebellum. Moreover, SHANK2 acts as a component of the albumin endocytic pathway in podocytes, and regulates renal albumin endocytosis. It also associates with and regulates Na+/H+ exchanger 3 (NHE3) and is involved in the fine regulation of transepithelial salt and water transport through affecting NHE3 expression and activity. Mutations in the SHANK2 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation. SHANK2 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also termed DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   73 MVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYPQSFEKGVPYL 152
Cdd:cd17176     3 LVIRIIIPDLQQTKCIRFNPDATVWVAKQRILCTLNQSLKDVLNYGLFQPASNGRDGKFLDEERLLREYPQPVNKGVPSL 82

                  ....*
gi 768009462  153 EFRYK 157
Cdd:cd17176    83 EFRYK 87

FERM (Four.1 protein, Ezrin, Radixin, Moesin) domain, F0 sub-domain, found in SH3 and multiple ankyrin repeat domains protein 3 (SHANK3); SHANK3, also termed proline-rich synapse-associated protein 2 (ProSAP2), is a postsynaptic density (PSD)-associated scaffolding protein at the excitatory synapse that interconnects neurotransmitter receptors and cell adhesion molecules by direct and indirect interactions with numerous other PSD-associated proteins. It is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. It is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic strength. Mutations in the SHANK3 synaptic scaffolding gene may lead to autism spectrum disorder and mental retardation, and the cause of human Phelan-McDermid syndrome (22q13.3 deletion syndrome) has been isolated to loss of function of one copy of the SHANK3 gene. SHANK3 contains an N-terminal F0 domain of FERM (Band 4.1, ezrin, radixin, moesin), six ankyrin (ANK) repeats, one SH3 (Src homology 3) domain, one PDZ (PSD-95, Dlg, and ZO-1/2, also known as DHR or GLGF) domain, and a C-terminal SAM (sterile alpha motif) domain. This family corresponds to the F0 domain that adopts a ubiquitin-like fold.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   73 MVFRIGIPDLHQTKCLRFNPDATIWTAKQQVLCALSESLQDVLNYGLFQPATSGRDANFLEEERLLREYPQSFEKGVPYL 152
Cdd:cd17177     2 LVVRIGIPDLQQTKCLRLNPDAPVWASKQRILCTLNHSLKDVLNYGLFQPAFNGRAGKFLDEERLLREYPLPLDTPVPYL 81

                  ....*
gi 768009462  153 EFRYK 157
Cdd:cd17177    82 EFRYK 86

Ankyrin repeat [Signal transduction mechanisms];

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  166 LDEKQLAKLHTKTGLKKFLEYVQLGTSDKVARLLDKGLDPNYHDSDSGETPLTLAAQtEGSVEVIRTLCLGGAHIDFRAR 245
Cdd:COG0666    40 LLLALLALALADALGALLLLAAALAGDLLVALLLLAAGADINAKDDGGNTLLHAAAR-NGDLEIVKLLLEAGADVNARDK 118

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  246 DGMTALHKAACARHCLALTALLDLGGSPNYKDRRGLTPLfHTAMVGGDPRCCELLLFNRAQLGIADENGWQEIHQACQRG 325
Cdd:COG0666   119 DGETPLHLAAYNGNLEIVKLLLEAGADVNAQDNDGNTPL-HLAAANGNLEIVKLLLEAGADVNARDNDGETPLHLAAENG 197

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  326 HSQHLEHLLFYGAEPGAQNASGNTALHICALYNKETCARILLYRGADKDVKNNNGQTPFQVAVIAGNFELGELIRNHREQ 405
Cdd:COG0666   198 HLEIVKLLLEAGADVNAKDNDGKTALDLAAENGNLEIVKLLLEAGADLNAKDKDGLTALLLAAAAGAALIVKLLLLALLL 277

                  ..
gi 768009462  406 DV 407
Cdd:COG0666   278 LA 279

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 1; Shank1, also called SSTRIP (Somatostatin receptor-interacting protein), is a brain-specific protein that plays a role in the construction of postsynaptic density (PSD) and the maturation of dendritic spines. Mice deficient in Shank1 show altered PSD composition, thinner PSDs, smaller dendritic spines, and weaker basal synaptic transmission, although synaptic plasticity is normal. They show increased anxiety and impaired fear memory, but also show better spatial learning. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  557 RSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCL 608
Cdd:cd11982     1 RTFMAVKPYQSQAEGEISLSKGEKIKVLSVGEGGFWEGQVKGRVGWFPSDCV 52

Src homology 3 domain of SH3 and multiple ankyrin repeat domains (Shank) proteins; Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. They bind a variety of membrane and cytosolic proteins, and exist in alternatively spliced isoforms. They are highly enriched in postsynaptic density (PSD) where they interact with the cytoskeleton and with postsynaptic membrane receptors including NMDA and glutamate receptors. They are crucial in the construction and organization of the PSD and dendritic spines of excitatory synapses. There are three members of this family (Shank1, Shank2, Shank3) which show distinct and cell-type specific patterns of expression. Shank1 is brain-specific; Shank2 is found in neurons, glia, endocrine cells, liver, and kidney; Shank3 is widely expressed. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  558 SFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDC 607
Cdd:cd11832     1 YFIAVKSYSPQEEGEISLHKGDRVKVLSIGEGGFWEGSVRGRTGWFPSDC 50

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 3; Shank3, also called ProSAP2 (Proline-rich synapse-associated protein 2), is widely expressed. It plays a role in the formation of dendritic spines and synapses. Haploinsufficiency of the Shank3 gene causes the 22q13 deletion/Phelan-McDermid syndrome, and variants of Shank3 have been implicated in autism spectrum disorder, schizophrenia, and intellectual disability. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  557 RSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCL 608
Cdd:cd11984     1 RTFIAVKAYSPQGEGEIQLNRGERVKVLSIGEGGFWEGTVKGRTGWFPADCV 52

Src homology 3 domain of SH3 and multiple ankyrin repeat domains protein 2; Shank2, also called ProSAP1 (Proline-rich synapse-associated protein 1) or CortBP1 (Cortactin-binding protein 1), is found in neurons, glia, endocrine cells, liver, and kidney. It plays a role in regulating dendritic spine volume and branching and postsynaptic clustering. Mutations in the Shank2 gene are associated with autism spectrum disorder and mental retardation. Shank proteins carry scaffolding functions through multiple sites of protein-protein interaction in its domain architecture, including ankyrin (ANK) repeats, a long proline rich region, as well as SH3, PDZ, and SAM domains. The SH3 domain of Shank binds GRIP, a scaffold protein that binds AMPA receptors and Eph receptors/ligands. 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 768009462  557 RSFMAVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCL 608
Cdd:cd11983     1 RHFVVVKSYQPQVEGEIPLHKGDRVKVLSIGEGGFWEGSARGHVGWFPAECV 52

PDZ domains of the Na+/H+ exchange regulatory cofactor (NHERF) family (NHERF1-4), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of the Na+/H+ exchange regulatory cofactor (NHERF) family of multi-PDZ-domain-containing scaffolding proteins (NHERF1-4), and related domains. The NHERF family includes NHERF1 (also known as EBP50), NHERF2 (also known as E3KARP; TKA-1; SIP-1), NHERF3 (also known as CAP70; CLAMP; Napi-Cap-1; PDZD1) and NHERF4 (also known as IKEPP; PDZK2; Napi-Cap-2). NHERF1 and NHERF2 have tandem PDZ domains (PDZ1-2); NHERF3 and NHERF4 have four PDZ domains (PDZ1-4). NHERFs are involved in the regulation of multiple receptors or transporters, such as type II sodium-phosphate cotransporter (Npt2a), purinergic P2Y1 receptor P2Y1R, the beta2-adrenergic receptor (beta2-AR), parathyroid hormone receptor type 1 (PTHR), the lysophosphatidic acid receptors (LPARs), sodium-hydrogen exchanger 3 (NHE3), and cystic fibrosis transmembrane conductance regulator (CFTR). NHERF-PDZ1 domain interaction partners include Npt2a, purinergic P2Y1 receptor, beta2-AR, CFTR, PTHR, NH3, G-protein-coupled receptor kinase 6 (GRK6A), platelet-derived growth factor receptor (PDGFR), B1 subunit of the H+ATPase, cholesterol, receptor for activated C-kinase RACK1, aquaporin 9, among others. The NHERF PDZ2 domain interacts with fewer proteins: NHERF1 PDZ2 binds Npt2a, PTHR, beta-catenin, aquaporin 9, and RACK1; NHERF2 PDZ2 binds LPA2, P2Y1R, and NHE3, cGMP-dependent protein kinase type II (cGKII). NHERF4 PDZ1 and PDZ4 bind the epithelial Ca(2+) channels TRPV5 and TRPV6. NHERF2/NHERF3 heterodimerization is mediated by PDZ domains of NHERF2 and the C-terminal PDZ domain recognition motif of NHERF3. NHERF4 regulates several transporters mediating influx of xenobiotics and nutrients in the small intestine. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This NHERF-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  659 KKDSEGFGFVLRGAKAQTpieeftptpafpaLQYLESVDEGGVAWRAGLRMGDFLIEVNGQNVVKVGHRQVVNMIRQGGN 738
Cdd:cd06768     6 VKGPEGYGFNLHAEKGRP-------------GHFIREVDPGSPAERAGLKDGDRLVEVNGENVEGESHEQVVEKIKASGN 72

                  ....*..
gi 768009462  739 TLMVKVV 745
Cdd:cd06768    73 QVTLLVV 79

canonical PDZ domain; Canonical PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain. PDZ domains usually bind to short specific peptide sequences located at the C-terminal end of their partner proteins known as PDZ binding motifs. These domains can also interact with internal peptide motifs and certain lipids, and can take part in a head-to-tail oligomerization with other PDZ domains. The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. The canonical PDZ domain contains six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  654 TVLLQKKDSEGFGFVLRGAKAQ-TPIeeftptpafpalqYLESVDEGGVAWRAG-LRMGDFLIEVNGQNVVKVGHRQVVN 731
Cdd:cd00136     1 TVTLEKDPGGGLGFSIRGGKDGgGGI-------------FVSRVEPGGPAARDGrLRVGDRILEVNGVSLEGLTHEEAVE 67

                          90
                  ....*....|....
gi 768009462  732 MIRQGGNTLMVKVV 745
Cdd:cd00136    68 LLKSAGGEVTLTVR 81

PDZ domain of tamalin, cytohesin-1-interacting protein (CYTIP), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of tamalin, cytohesin-1-interacting protein, and related domains. Tamalin (trafficking regulator and scaffold protein tamalin, also known as general receptor for phosphoinositides 1-associated scaffold protein, GRASP) functions to link receptors, including group 1 metabotropic glutamate receptors (mGluRs), to neuronal proteins. The tamalin PDZ domain binds the C-terminal domains of group I mGluRs; it also binds potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2), neurotrophin-3 (NT3) TrkCT1-truncated receptor, SAP90/PSD-95-associated protein, and tamalin itself. CYTIP (cytohesin-1-interacting protein, also known as Pleckstrin homology Sec7 and coiled-coil domain-binding protein) sequesters cytohesin-1 in the cytoplasm, limiting its interaction with beta2 integrins; cytohesin-1 binds the CYTIP coiled coil domain. The CYTIP PDZ domain can bind the C-terminal peptide of protocadherin alpha-1 (PCDHA1), indicating a possible interaction between the two. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This tamalin-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

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                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  651 KEKTVLLQKKDSEGFGFVLrgakaQTPIEEFTPTPAFPALQYLESVDEGGVAWRAGLRMGDFLIEVNGQNVVKVGHRQVV 730
Cdd:cd06713     2 QRRTIILEKQDNETFGFEI-----QTYGLHHKNSNEVEMCTYVCRVHEDSPAYLAGLTAGDVILSVNGVSVEGASHQEIV 76

                          90
                  ....*....|....*
gi 768009462  731 NMIRQGGNTLMVKVV 745
Cdd:cd06713    77 ELIRSSGNTLRLETL 91

SAM (Sterile alpha motif ); SAM (Sterile Alpha Motif) domain is a module consisting of approximately 70 amino acids. This domain is found in the Fungi/Metazoa group and in a restricted number of bacteria. Proteins with SAM domains are represented by a wide variety of domain architectures and have different intracellular localization, including nucleus, cytoplasm and membranes. SAM domains have diverse functions. They can interact with proteins, RNAs and membrane lipids, contain site of phosphorylation and/or kinase docking site, and play a role in protein homo and hetero dimerization/oligomerization in processes ranging from signal transduction to regulation of transcription. Mutations in SAM domains have been linked to several diseases.

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                  ....*....|....*....|....*....|....*....|....*....|....*
gi 768009462 2093 DVADWLEWLGLAEHRAQFLDHEIDGSHLPALTKEDYVDLGVTRVGHRMNIDRALK 2147
Cdd:cd09487     1 DVAEWLESLGLEQYADLFRKNEIDGDALLLLTDEDLKELGITSPGHRKKILRAIQ 55

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   318 IHQACQRGHSQHLEHLLFYGAEPGAQNASGNTALHICALYNKETCARILLyRGADKDVKnNNGQTPFQVAVIAGNFELGE 397
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLL-EHADVNLK-DNGRTALHYAARSGHLEIVK 78

                   ....*
gi 768009462   398 LIRNH 402
Cdd:pfam12796   79 LLLEK 83

PDZ domain 2 of delphilin (L-delphilin isoform), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain 2 of delphilin (also known as glutamate receptor, ionotropic, delta 2-interacting protein 1, L-delphilin). Delphilin, a postsynaptic protein which it is selectively expressed at cerebellar Purkinje cells, links the glutamate receptor delta 2 subunit (GluRdelta2) with the actin cytoskeleton and various signaling molecules. Two alternatively spliced isoforms of delphilin have been characterized: L-delphilin has two PDZ domains, PDZ1 and PDZ2, and S-delphilin has a single PDZ domain (PDZ2). These two isoforms are differently palmitoylated and may be involved in controlling GluRdelta2 signaling in Purkinje cells. PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This delphilin-like family PDZ2 domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  658 QKKDSEGFGFVLRGakaQTPIeeftptpafpalqYLESVDEGGVAWRAGLRMGDFLIEVNGQNVVKVGHRQVVNMIRQGG 737
Cdd:cd06744     4 VYRGNGSFGFTLRG---HAPV-------------YIESVDPGSAAERAGLKPGDRILFLNGLDVRNCSHDKVVSLLQGSG 67

                  ....*..
gi 768009462  738 N--TLMV 742
Cdd:cd06744    68 SmpTLVV 74

Variant SH3 domain; SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organization. First described in the Src cytoplasmic tyrosine kinase. The structure is a partly opened beta barrel.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 768009462   561 AVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCLEEV 611
Cdd:pfam07653    4 VIFDYVGTDKNGLTLKKGDVVKVLGKDNDGWWEGETGGRVGLVPSTAVEEI 54

Ankyrin repeats (3 copies);

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462   285 FHTAMVGGDPRCCELLLFNRAQLGIADENGWQEIHQACQRGHSQHLEHLLFYGAepGAQNASGNTALHICALYNKETCAR 364
Cdd:pfam12796    1 LHLAAKNGNLELVKLLLENGADANLQDKNGRTALHLAAKNGHLEIVKLLLEHAD--VNLKDNGRTALHYAARSGHLEIVK 78

                           90
                   ....*....|...
gi 768009462   365 ILLYRGADKDVKN 377
Cdd:pfam12796   79 LLLEKGADINVKD 91

Src Homology 3 domain of Pak Interactive eXchange factors; PIX proteins are Rho guanine nucleotide exchange factors (GEFs), which activate small GTPases by exchanging bound GDP for free GTP. They act as GEFs for both Cdc42 and Rac 1, and have been implicated in cell motility, adhesion, neurite outgrowth, and cell polarity. Vertebrates contain two proteins from the PIX subfamily, alpha-PIX and beta-PIX. Alpha-PIX, also called ARHGEF6, is localized in dendritic spines where it regulates spine morphogenesis. Mutations in the ARHGEF6 gene cause X-linked intellectual disability in humans. Beta-PIX play roles in regulating neuroendocrine exocytosis, focal adhesion maturation, cell migration, synaptic vesicle localization, and insulin secretion. PIX proteins contain an N-terminal SH3 domain followed by RhoGEF (also called Dbl-homologous or DH) and Pleckstrin Homology (PH) domains, and a C-terminal leucine-zipper domain for dimerization. The SH3 domain of PIX binds to an atypical PxxxPR motif in p21-activated kinases (PAKs) with high affinity. The binding of PAKs to PIX facilitate the localization of PAKs to focal complexes and also localizes PAKs to PIX targets Cdc43 and Rac, leading to the activation of PAKs. 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 768009462  561 AVKSYQAQAEGEISLSKGEKIKVLSIGEGGFWEGQVKGRVGWFPSDCLEE 610
Cdd:cd11877     4 AKFNFEGTNEDELSFDKGDIITVTQVVEGGWWEGTLNGKTGWFPSNYVKE 53

PDZ domain of DEP domain-containing mTOR-interacting protein (DEPTOR), and related domains; PDZ (PSD-95 (Postsynaptic density protein 95), Dlg (Discs large protein), and ZO-1 (Zonula occludens-1)) domain of DEPTOR, and related domains. DEPTOR (also known as DEP domain-containing protein 6, DEP6) is a regulatory protein of mTOR signaling; it is a negative regulator of both the mTORC1 and mTORC2 signaling pathways. DEPTOR's PDZ domain binds to mTOR's FAT domain to suppress mTOR's kinase activity. The DEPTOR PDZ domain also binds lysine-specific demethylase 4A (KDM4A), leucine-rich repeat containing 4 (LRRC4), p38gamma, and major intrinsically disordered Notch2-binding receptor 1 (MINAR1, also known as Ubtor). DEPTOR also interacts with salt-inducible kinase 3 (SIK3). PDZ domains usually bind in a sequence-specific manner to short peptide sequences located at the C-terminal end of their partner proteins (known as PDZ binding motifs). The PDZ superfamily includes canonical PDZ domains as well as those with circular permutations and domain swapping mediated by beta-strands. This DEPTOR-like family domain is a canonical PDZ domain containing six beta-strands A-F and two alpha-helices (alpha-helix 1 and 2), arranged in the order: beta-strands A, B, C, alpha-helix 1, beta-strands D, E, alpha-helix 2 and beta-strand F.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  661 DSEGFGFVLRGAKaqtPIeeftptpafpalqYLESVDEGGVAWRAGLRMGDFLIEVNGQNVVKVGHRQVVNMIRQGGNTL 740
Cdd:cd23067     7 DAVGWGFVVRGSK---PC-------------HIQAVDPSGPAAAAGMKVCQFIVSVNGLNVLHMDHRTVSNLILTGPRTI 70

                  ....
gi 768009462  741 MVKV 744
Cdd:cd23067    71 VMEV 74

Transient Receptor Potential channel, Vanilloid subfamily (TRPV), types 5 and 6; TRPV5 and TRPV6 (TRPV5/6) are two homologous members within the vanilloid subfamily of the transient receptor potential (TRP) family. TRPV5 and TRPV6 show only 30-40% homology with other members of the TRP family and have unique properties that differentiates them from other TRP channels. They mediate calcium uptake in epithelia and their expression is dramatically increased in numerous types of cancer. The structure of TRPV5/6 shows the typical topology features of all TRP family members, such as six transmembrane regions, a short hydrophobic stretch between transmembrane segments 5 and 6, which is predicted to form the Ca2+ pore, and large intracellular N- and C-terminal domains. The N-terminal domain of TRPV5/6 contains three ankyrin repeats. This structural element is present in several proteins and plays a role in protein-protein interactions. The N- and C-terminal tails of TRPV5/6 each contain an internal PDZ motif which can function as part of a molecular scaffold via interaction with PDZ-domain containing proteins. A major difference between the properties of TRPV5 and TRPV6 is in their tissue distribution: TRPV5 is predominantly expressed in the distal convoluted tubules (DCT) and connecting tubules (CNT) of the kidney, with limited expression in extrarenal tissues. In contrast, TRPV6 has a broader expression pattern such as expression in the intestine, kidney, placenta, epididymis, exocrine tissues, and a few other tissues.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  214 ETPLTLAAQtEGSVEVIRTLcLGGAHIDFRARDGM--TALHKAACARHCLALTALLDlgGSPN----------YKdrrGL 281
Cdd:cd22192    18 ESPLLLAAK-ENDVQAIKKL-LKCPSCDLFQRGALgeTALHVAALYDNLEAAVVLME--AAPElvnepmtsdlYQ---GE 90

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 768009462  282 TPLfHTAMV-------------GGD---PRCC---------ELLLFNRAQLGIAdengwqeihqACQrGHSQHLEHLLFY 336
Cdd:cd22192    91 TAL-HIAVVnqnlnlvreliarGADvvsPRATgtffrpgpkNLIYYGEHPLSFA----------ACV-GNEEIVRLLIEH 158

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 768009462  337 GAEPGAQNASGNTALHICALYNKETCAR-----ILLYRGADKD-----VKNNNGQTPFQVAVIAGNFELGE-LIRNHR 403
Cdd:cd22192   159 GADIRAQDSLGNTVLHILVLQPNKTFACqmydlILSYDKEDDLqpldlVPNNQGLTPFKLAAKEGNIVMFQhLVQKRR 236