Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619    160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 239
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 4504619    240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Insulin-like growth factor binding protein;

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4504619      30 DTCGPCEPASCPPLPPLGCLLgETRDACGCCPMCARgegEPCGGGGAGRGYCAPGMECVKS 90
Cdd:smart00121   1 ARCPPCDPARCPPCPPGCAEL-VRLDGCGCCPVCAR---QEGEPCGVYTPRCAPGLRCQPP 57

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619    160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 239
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 4504619    240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrgHYGVQrteLLPGDRDNLAIQTRGgpeKHEVtgwvLVSPLS 239
Cdd:cd05744   1 PHFLQAPGDLEVQEGRLCRFDCKVSGLPTPDLFWQ-----LNGKP---VRPDSAHKMLVRENG---RHSL----IIEPVT 65

                        90       100
                ....*....|....*....|....*.
gi 4504619  240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd05744  66 KRDAGIYTCIARNRAGENSFNAELVV 91

Kazal type serine protease inhibitors and follistatin-like domains. Kazal inhibitors inhibit serine proteases, such as, trypsin, chyomotrypsin, avian ovomucoids, and elastases. The inhibitory domain has one reactive site peptide bond, which serves the cognate enzyme as substrate. The reactive site peptide bond is a combining loop which has an identical conformation in all Kazal inhibitors and in all enzyme/inhibitor complexes. These Kazal domains (small hydrophobic core of alpha/beta structure with 3 to 4 disulfide bonds) often occur in tandem arrays. Similar domains are also present in follistatin (FS) and follistatin-like family members, which play an important role in tissue specific regulation. The FS domain consists of an N-terminal beta hairpin (FOLN/EGF-like domain) and a Kazal-like domain and has five disulfide bonds. Although the Kazal-like FS substructure is similar to Kazal proteinase inhibitors, no FS domain has yet been shown to be a proteinase inhibitor. Follistatin-like family members include SPARC, also known as, BM-40 or osteonectin, the Gallus gallus Flik protein, as well as, agrin which has a long array of FS domains. The kazal-type inhibitor domain has also been detected in an extracellular loop region of solute carrier 21 (SLC21) family members (organic anion transporters) , which may regulate the specificity of anion uptake. The distant homolog, Ascidian trypsin inhibitor, is included in this CD.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*
gi 4504619  113 CKSRY-PVCGSDGTTYPSGCQLRaasqRAESRGEKAITQVSKGTC 156
Cdd:cd00104   1 CPKEYdPVCGSDGKTYSNECHLG----CAACRSGRSITVAHNGPC 41

Insulin growth factor-binding protein homologues; High affinity binding partners of insulin-like growth factors.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4504619      30 DTCGPCEPASCPPLPPLGCLLgETRDACGCCPMCARgegEPCGGGGAGRGYCAPGMECVKS 90
Cdd:smart00121   1 ARCPPCDPARCPPCPPGCAEL-VRLDGCGCCPVCAR---QEGEPCGVYTPRCAPGLRCQPP 57

Immunoglobulin I-set domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619    160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELLPGDRdnLAIQTRGGpeKHEVTgwvlVSPLS 239
Cdd:pfam07679   1 PKFTQKPKDVEVQEGESARFTCTVTGTPDPEVSWFK--------DGQPLRSSDR--FKVTYEGG--TYTLT----ISNVQ 64

                          90       100
                  ....*....|....*....|....*.
gi 4504619    240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:pfam07679  65 PDDSGKYTCVATNSAGEAEASAELTV 90

Immunoglobulin (Ig)-like domain of myotilin, palladin, and myopalladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the immunoglobulin (Ig)-like domain in myotilin, palladin, and myopalladin. Myotilin, palladin, and myopalladin function as scaffolds that regulate actin organization. Myotilin and myopalladin are most abundant in skeletal and cardiac muscle; palladin is ubiquitously expressed in the organs of developing vertebrates and plays a key role in cellular morphogenesis. The three family members each interact with specific molecular partners with all three binding to alpha-actinin; In addition, palladin also binds to vasodilator-stimulated phosphoprotein (VASP) and ezrin, myotilin binds to filamin and actin, and myopalladin also binds to nebulin and cardiac ankyrin repeat protein (CARP). This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrgHYGVQrteLLPGDRDNLAIQTRGgpeKHEVtgwvLVSPLS 239
Cdd:cd05744   1 PHFLQAPGDLEVQEGRLCRFDCKVSGLPTPDLFWQ-----LNGKP---VRPDSAHKMLVRENG---RHSL----IIEPVT 65

                        90       100
                ....*....|....*....|....*.
gi 4504619  240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd05744  66 KRDAGIYTCIARNRAGENSFNAELVV 91

Immunoglobulin domain; This family contains immunoglobulin-like domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619    160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgDRDNLAIQTRGGPEKHEVTGWVLVSPLS 239
Cdd:pfam13927   2 PVITVSPSSVTVREGETVTLTCEATGSPPPTITWYK----------------NGEPISSGSTRSRSLSGSNSTLTISNVT 65

                          90
                  ....*....|...
gi 4504619    240 KEDAGEYECHASN 252
Cdd:pfam13927  66 RSDAGTYTCVASN 78

Second Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the titin Z1z2 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghygvQRTELlpgdRDNLAIQTRGGPEKHEVtgwvLVSPLS 239
Cdd:cd20972   2 PQFIQKLRSQEVAEGSKVRLECRVTGNPTPVVRWFC--------EGKEL----QNSPDIQIHQEGDLHSL----IIAEAF 65

                        90       100
                ....*....|....*....|....*.
gi 4504619  240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd20972  66 EEDTGRYSCLATNSVGSDTTSAEIFV 91

Immunoglobulin domain; The members here are composed of the immunoglobulin (Ig) domain found in the Ig superfamily. The Ig superfamily is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. Members of this group are components of immunoglobulin, neuroglia, cell surface glycoproteins, including T-cell receptors, CD2, CD4, CD8, and membrane glycoproteins, including butyrophilin and chondroitin sulfate proteoglycan core protein. A predominant feature of most Ig domains is a disulfide bridge connecting the two beta-sheets with a tryptophan residue packed against the disulfide bond. Ig superfamily (IgSF) domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Typically, the V-set domains have A, B, E, and D strands in one sheet and A', G, F, C, C' and C" in the other. The structures in C1-set are smaller than those in the V-set; they have one beta sheet that is formed by strands A, B, E, and D and the other by strands G, F, C, and C'. Moreover, a C1-set Ig domain contains a short C' strand (three residues) and lacks A' and C" strand. Unlike other Ig domain sets, C2-set structures do not have a D strand. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  177 VYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgDRDNLAIQTRGGPEKHEVTGWVLVSPLSKEDAGEYECHASNS-QG 255
Cdd:cd00096   1 VTLTCSASGNPPPTITWYK----------------NGKPLPPSSRDSRRSELGNGTLTISNVTLEDSGTYTCVASNSaGG 64

                ....*.
gi 4504619  256 QASASA 261
Cdd:cd00096  65 SASASV 70

Fifth Ig-like domain of Roundabout (Robo) homolog 1/2, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the fifth Ig-like domain of Roundabout (Robo) homolog 1/2 and similar domains. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, -2, and -3), and three mammalian Slit homologs (Slit-1,-2, -3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, -2, and -3 are expressed by commissural neurons in the vertebrate spinal cord and Slits 1, -2, -3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of slit responsiveness, antagonizes slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be is the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. The fifth Ig-like domain of Robo 1 and 2 is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  162 IVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWnkVKRGHygvqrTELLPGDR----DNLAIQTRGgpekhevtgwvlvsp 237
Cdd:cd20952   2 ILQGPQNQTVAVGGTVVLNCQATGEPVPTISW--LKDGV-----PLLGKDERittlENGSLQIKG--------------- 59

                        90       100
                ....*....|....*....|....*...
gi 4504619  238 LSKEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd20952  60 AEKSDTGEYTCVALNLSGEATWSAVLDV 87

Second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor_like-1(FGFRL1); member of the I-set of IgSF domains; The members here are composed of the second immunoglobulin (Ig)-like domain of fibroblast growth factor (FGF) receptor like-1(FGFRL1). FGFRL1 is comprised of a signal peptide, three extracellular Ig-like modules, a transmembrane segment, and a short intracellular domain. FGFRL1 is expressed preferentially in skeletal tissues. Similar to FGF receptors, the expressed protein interacts specifically with heparin and with FGF2. FGFRL1 does not have a protein tyrosine kinase domain at its C-terminus; neither does its cytoplasmic domain appear to interact with a signaling partner. It has been suggested that FGFRL1 may not have any direct signaling function, but instead acts as a decoy receptor trapping FGFs and preventing them from binding other receptors.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  174 GAQVYLSCEVIGIPTPVLIWNKvkrghygvqrtellpgDRDNLAIQTRGGPEKHEvtgWVL-VSPLSKEDAGEYECHASN 252
Cdd:cd05856  19 GSSVRLKCVASGNPRPDITWLK----------------DNKPLTPPEIGENKKKK---WTLsLKNLKPEDSGKYTCHVSN 79

                        90
                ....*....|...
gi 4504619  253 SQGQASASAKITV 265
Cdd:cd05856  80 RAGEINATYKVDV 92

Third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the third immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, and Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  163 VTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvKRGHYGVQRTELLPgDRDnlaiqtrggpekhevtgwVLVSPLSKED 242
Cdd:cd05725   1 VKRPQNQVVLVDDSAEFQCEVGGDPVPTVRWRK-EDGELPKGRYEILD-DHS------------------LKIRKVTAGD 60

                        90       100
                ....*....|....*....|...
gi 4504619  243 AGEYECHASNSQGQASASAKITV 265
Cdd:cd05725  61 MGSYTCVAENMVGKIEASATLTV 83

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM), and similar domains; The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains and five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, and spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM and human neurofascin.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  174 GAQVYLSCEVIGIPTPVLIWNKVKrghygvqrTELLPGdrdnlaiqtRGGPEKHEVTgwVLVSPLSKEDAGEYECHASNS 253
Cdd:cd05731  10 GGVLLLECIAEGLPTPDIRWIKLG--------GELPKG---------RTKFENFNKT--LKIENVSEADSGEYQCTASNT 70

                        90
                ....*....|...
gi 4504619  254 QGqaSASAKITVV 266
Cdd:cd05731  71 MG--SARHTISVT 81

Second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the second immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of the Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, and Robo3), and three mammalian Slit homologs (Slit-1,Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit-2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  166 PKDIWNVTGAQVYLSCEV-IGIPTPVLIWNKvkrghygvqrtELLPGDRDNLAIQTRGGpekhevtGWVLVSPLSKEDAG 244
Cdd:cd05724   4 PSDTQVAVGEMAVLECSPpRGHPEPTVSWRK-----------DGQPLNLDNERVRIVDD-------GNLLIAEARKSDEG 65

                        90       100
                ....*....|....*....|..
gi 4504619  245 EYECHASNSQG-QASASAKITV 265
Cdd:cd05724  66 TYKCVATNMVGeRESRAARLSV 87

Second C-terminal immunoglobulin (Ig)-like domain of palladin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the C-terminal immunoglobulin (Ig)-like domain of palladin. Palladin belongs to the palladin-myotilin-myopalladin family. Proteins belonging to this family contain multiple Ig-like domains and function as scaffolds, modulating actin cytoskeleton. Palladin binds to alpha-actinin ezrin, vasodilator-stimulated phosphoprotein VASP, SPIN90 (also known as DIP or mDia interacting protein), and Src. Palladin also binds F-actin directly, via its Ig3 domain. Palladin is expressed as several alternatively spliced isoforms, having various combinations of Ig-like domains, in a cell-type-specific manner. It has been suggested that palladin's different Ig-like domains may be specialized for distinct functions. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNkvkrghygVQRTELLPGDRDNLAIQTRGgpekhevTGWVLVSPLS 239
Cdd:cd20990   1 PHFLQAPGDLTVQEGKLCRMDCKVSGLPTPDLSWQ--------LDGKPIRPDSAHKMLVRENG-------VHSLIIEPVT 65

                        90       100
                ....*....|....*....|....*.
gi 4504619  240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd20990  66 SRDAGIYTCIATNRAGQNSFNLELVV 91

C-terminal immunoglobulin (Ig)-like domain of myotilin; member of the I-set of Ig superfamily (IgSF) domains; The members here are composed of the C-terminal immunoglobulin (Ig)-like domain of myotilin. Mytolin belongs to the palladin-myotilin-myopalladin family. Proteins belonging to the latter family contain multiple Ig-like domains and function as scaffolds, modulating the actin cytoskeleton. Myotilin is most abundant in skeletal and cardiac muscle and is involved in maintaining sarcomere integrity. It binds to alpha-actinin, filamin, and actin. Mutations in myotilin lead to muscle disorders. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKrghygvqrtELLPGDRDNLAIQtrggpekHEVTGWV--LVSP 237
Cdd:cd05892   1 PMFIQKPQNKKVLEGDPVRLECQISAIPPPQIFWKKNN---------EMLQYNTDRISLY-------QDNCGRIclLIQN 64

                        90       100
                ....*....|....*....|....*...
gi 4504619  238 LSKEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd05892  65 ANKKDAGWYTVSAVNEAGVVSCNARLDV 92

Immunoglobulin (Ig)-like domain of Down Syndrome Cell Adhesion molecule (DSCAM); The members here are composed of the immunoglobulin (Ig)-like domain of Down Syndrome Cell Adhesion molecule (DSCAM). DSCAM is a cell adhesion molecule expressed largely in the developing nervous system. The gene encoding DSCAM is located at human chromosome 21q22, the locus associated with the intellectual disability phenotype of Down Syndrome. DSCAM is predicted to be the largest member of the IG superfamily. It has been demonstrated that DSCAM can mediate cation-independent homophilic intercellular adhesion.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVK-RGHYGVQRTELLPGdrdnlAIQTRGgpekhevTGWVLVSPL 238
Cdd:cd05734   2 PRFVVQPNDQDGIYGKAVVLNCSADGYPPPTIVWKHSKgSGVPQFQHIVPLNG-----RIQLLS-------NGSLLIKHV 69

                        90       100
                ....*....|....*....|....*...
gi 4504619  239 SKEDAGEYECHASNSQG-QASASAKITV 265
Cdd:cd05734  70 LEEDSGYYLCKVSNDVGaDISKSMYLTV 97

Kazal-type serine protease inhibitor domain; Usually indicative of serine protease inhibitors. However, kazal-like domains are also seen in the extracellular part of agrins, which are not known to be protease inhibitors. Kazal domains often occur in tandem arrays. Small alpha+beta fold containing three disulphides.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 4504619    111 CVCKSRY--PVCGSDGTTYPSGCQLRAASQRAeSRGEKAITQVSKGTC 156
Cdd:pfam07648   4 CQCPKTEyePVCGSDGVTYPSPCALCAAGCKL-GKEVKEEKVKYDGSC 50

First Ig-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins; a member of the I-set of IgSF domains; The members here are composed of the first immunoglobulin (Ig)-like domain of the giant muscle protein titin Z1z2 in the sarcomeric Z-disk and similar proteins. Titin is a key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The Ig superfamily (IgSF) is a heterogenous group of proteins, built on a common fold comprised of a sandwich of two beta sheets. IgSF domains can be divided into 4 main classes based on their structures and sequences: the Variable (V), Constant 1 (C1), Constant 2 (C2), and Intermediate (I) sets. Unlike the V-set, one of the distinctive features of I-set domains is the lack of a C" strand. The structure of the titin Z1z2 lacks this strand and thus it belongs to the I-set of the IgSF. I-set domains are found in several cell adhesion molecules (such as VCAM, ICAM, and MADCAM), and are also present in numerous other diverse protein families, including several tyrosine-protein kinase receptors, the hemolymph protein hemolin, the muscle proteins titin, telokin, and twitchin, the neuronal adhesion molecule axonin-1, and the signaling molecule semaphorin 4D that is involved in axonal guidance, immune function and angiogenesis.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKRghygVQRTELLPGdrdnLAIQTRGGPEKHEVTGwvlvspLS 239
Cdd:cd20974   1 PVFTQPLQSVVVLEGSTATFEAHVSGKPVPEVSWFRDGQ----VISTSTLPG----VQISFSDGRAKLSIPA------VT 66

                        90       100
                ....*....|....*....|....*.
gi 4504619  240 KEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd20974  67 KANSGRYSLTATNGSGQATSTAELLV 92

Seventh immunoglobulin domain of the Drosophila melanogaster Dscam protein, and similar domains; a member of the I-set of IgSF domains; The members here are composed of the seventh immunoglobulin domain of the Drosophila melanogaster Down syndrome cell adhesion molecule (DSCAM) protein and similar proteins. Down syndrome cell adhesion molecule (DSCAM) is a cell adhesion molecule that plays critical roles in neural development, including axon guidance and branching, axon target recognition, self-avoidance and synaptic formation. DSCAM belongs to the immunoglobulin superfamily and contributes to defects in the central nervous system in Down syndrome patients. Vertebrate DSCAMs differ from Drosophila Dscam1 in that they lack the extensive alternative splicing that occurs in the insect gene. Drosophila melanogaster Dscam has 38,016 isoforms generated by the alternative splicing of four variable exon clusters, which allows every neuron in the fly to display a distinctive set of Dscam proteins on its cell surface. Drosophila Dscam1 is a cell-surface protein that plays important roles in neural development and axon tiling of neurons. It is shown that thousands of isoforms bind themselves through specific homophilic (self-binding) interactions, a process which mediates cellular self-recognition. Drosophila Dscam2 is also alternatively spliced and plays a key role in the development of two visual system neurons, monopolar cells L1 and L2. This group is a member of the I-set Ig domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  160 PSIVTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKvkrghyGVQRTellPGDRDNLaiqtRGGPEKH-EVTGWVLVSPL 238
Cdd:cd20954   2 PRWIVEPVDANVAAGQDVMLHCQADGFPTPTVTWKK------ATGST---PGEYKDL----LYDPNVRiLPNGTLVFGHV 68

                        90
                ....*....|....*..
gi 4504619  239 SKEDAGEYECHASNSQG 255
Cdd:cd20954  69 QKENEGHYLCEAKNGIG 85

Immunoglobulin V-set domain; This domain is found in antibodies as well as neural protein P0 and CTL4 amongst others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619    164 TPPKDIWNVTGAQVYLSCEV---IGIPTPVLIWNKVKRG--------HYGVQRTELLPGDRdnlaIQTRGGPEKHEVTgw 232
Cdd:pfam07686   1 QTPREVTVALGGSVTLPCTYsssMSEASTSVYWYRQPPGkgptfliaYYSNGSEEGVKKGR----FSGRGDPSNGDGS-- 74

                          90       100       110
                  ....*....|....*....|....*....|....*
gi 4504619    233 VLVSPLSKEDAGEYECH-ASNSQGQASASAKITVV 266
Cdd:pfam07686  75 LTIQNLTLSDSGTYTCAvIPSGEGVFGKGTRLTVL 109

Fourth Ig domain of the neural cell adhesion molecule contactin-2, and similar domains; The members here are composed of the fourth Ig domain of the neural cell adhesion molecule contactin-2. Contactins are comprised of six Ig domains followed by four fibronectin type III (FnIII) domains anchored to the membrane by glycosylphosphatidylinositol. Contactin-2 (also called TAG-1, axonin-1) facilitates cell adhesion by homophilic binding between molecules in apposed membranes. The first four Ig domains form the intermolecular binding fragment which arranges as a compact U-shaped module by contacts between Ig domains 1 and 4, and domains 2 and 3. It has been proposed that a linear zipper-like array forms, from contactin-2 molecules alternatively provided by the two apposed membranes.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  166 PKDIWNVTGAQVYLSCEVIGIPTPVLIWnkVKRGhygvqrtELLPGDRDnlaIQTRGGPekhevtgwVLVSPLSKEDAGE 245
Cdd:cd05728   6 ISDTEADIGSSLRWECKASGNPRPAYRW--LKNG-------QPLASENR---IEVEAGD--------LRITKLSLSDSGM 65

                        90       100
                ....*....|....*....|
gi 4504619  246 YECHASNSQGQASASAKITV 265
Cdd:cd05728  66 YQCVAENKHGTIYASAELAV 85

Third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM); The members here are composed of the third immunoglobulin (Ig)-like domain of the L1 cell adhesion molecule (CAM). L1 belongs to the L1 subfamily of cell adhesion molecules (CAMs) and is comprised of an extracellular region having six Ig-like domains, five fibronectin type III domains, a transmembrane region and an intracellular domain. L1 is primarily expressed in the nervous system and is involved in its development and function. L1 is associated with an X-linked recessive disorder, X-linked hydrocephalus, MASA syndrome, or spastic paraplegia type 1, that involves abnormalities of axonal growth. This group also contains the chicken neuron-glia cell adhesion molecule, Ng-CAM.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  174 GAQVYLSCEVIGIPTPVLIWNKVkrghygvqrTELLPGDRdnlaiqtrGGPEKHevTGWVLVSPLSKEDAGEYECHASNS 253
Cdd:cd05876  10 GQSLVLECIAEGLPTPTVKWLRP---------SGPLPPDR--------VKYQNH--NKTLQLLNVGESDDGEYVCLAENS 70

                        90
                ....*....|..
gi 4504619  254 QGQASASAKITV 265
Cdd:cd05876  71 LGSARHAYYVTV 82

Fourth immunoglobulin (Ig)-like domain in Robo (roundabout) receptors; member of the I-set of Ig superfamily (IgSF) domains; Members here are composed the fourth immunoglobulin (Ig)-like domain in Robo (roundabout) receptors. Robo receptors play a role in the development of the central nervous system (CNS), and are receptors of Slit protein. Slit is a repellant secreted by the neural cells in the midline. Slit acts through Robo to prevent most neurons from crossing the midline from either side. Three mammalian Robo homologs (Robo1, Robo2, Robo3), and three mammalian Slit homologs (Slit-1, Slit-2, Slit-3), have been identified. Commissural axons, which cross the midline, express low levels of Robo; longitudinal axons, which avoid the midline, express high levels of Robo. Robo1, Robo2, and Robo3 are expressed by commissural neurons in the vertebrate spinal cord and Slit-1, Slit-2, and Slit-3 are expressed at the ventral midline. Robo-3 is a divergent member of the Robo family which instead of being a positive regulator of Slit responsiveness, antagonizes Slit responsiveness in precrossing axons. The Slit-Robo interaction is mediated by the second leucine-rich repeat (LRR) domain of Slit and the two N-terminal Ig domains of Robo, Ig1 and Ig2. The primary Robo binding site for Slit2 has been shown by surface plasmon resonance experiments and mutational analysis to be the Ig1 domain, while the Ig2 domain has been proposed to harbor a weak secondary binding site. This group belongs to the I-set of IgSF domains, having A-B-E-D strands in one beta-sheet and A'-G-F-C-C' in the other. Like the V-set Ig domains, members of the I-set have a discontinuous A strand, but lack a C" strand.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 4504619  163 VTPPKDIWNVTGAQVYLSCEVIGIPTPVLIWNKVKRGHYGVQRTELLPGDRDNLAiqtrggpekheVTGWVLVSPLSKED 242
Cdd:cd05726   3 VVKPRDQVVALGRTVTFQCETKGNPQPAIFWQKEGSQNLLFPYQPPQPSSRFSVS-----------PTGDLTITNVQRSD 71

                        90       100
                ....*....|....*....|....*..
gi 4504619  243 AGEYECHASNSQGQASASAKITVVDAL 269
Cdd:cd05726  72 VGYYICQALNVAGSILAKAQLEVTDVL 98

Immunoglobulin (Ig)-like domain in neuregulins; The members here are composed of the immunoglobulin (Ig)-like domain in neuregulins (NRGs). NRGs are signaling molecules which participate in cell-cell interactions in the nervous system, breast, heart, and other organ systems, and are implicated in the pathology of diseases including schizophrenia, multiple sclerosis, and breast cancer. There are four members of the neuregulin gene family (NRG-1, NRG-2, NRG-3, and NRG-4). The NRG-1 protein, binds to and activates the tyrosine kinases receptors ErbB3 and ErbB4, initiating signaling cascades. The other NRGs proteins bind one or the other or both of these ErbBs. NRG-1 has multiple functions: in the brain it regulates various processes such as radial glia formation and neuronal migration, dendritic development, and expression of neurotransmitters receptors, while in the peripheral nervous system NRG-1 regulates processes such as target cell differentiation, and Schwann cell survival. There are many NRG-1 isoforms which arise from the alternative splicing of mRNA. Less is known of the functions of the other NRGs. NRG-2 and NRG-3 are expressed predominantly in the nervous system. NRG-2 is expressed by motor neurons and terminal Schwann cells, and is concentrated near synaptic sites and may be a signal that regulates synaptic differentiation. NRG-4 has been shown to direct pancreatic islet cell development towards the delta-cell lineage.

                        10        20        30        40
                ....*....|....*....|....*....|....*....|....*...
gi 4504619  218 IQTRGGPEKHEVTgwvlVSPLSKEDAGEYECHASNSQGQASASAKITV 265
Cdd:cd05750  49 IKIRNKKKNSELQ----INKAKLEDSGEYTCVVENILGKDTVTGNVTV 92

Insulin growth factor-binding protein homologues; High affinity binding partners of insulin-like growth factors.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 4504619      30 DTCGPCEPASCPPLPPLGCLLgETRDACGCCPMCARgegEPCGGGGAGRGYCAPGMECVKS 90
Cdd:smart00121   1 ARCPPCDPARCPPCPPGCAEL-VRLDGCGCCPVCAR---QEGEPCGVYTPRCAPGLRCQPP 57

Solute carrier organic anion transporters of the Major Facilitator Superfamily of transporters; Solute carrier organic anion transporters (SLCOs) are also called organic anion transporting polypeptides (OATPs) or SLC21 (Solute carrier family 21) proteins. They are sodium-independent transporters that mediate the transport of a broad range of endo- as well as xenobiotics. Their substrates are mainly amphipathic organic anions with a molecular weight of more than 300Da, although there are a few known neutral or positively charged substrates. These include drugs including statins, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, antibiotics, antihistaminics, antihypertensives, and anticancer drugs. SLCOs/OATPs can be classified into 6 families (SLCO1-6 or OATP1-6) and each family may have subfamilies (e.g. OATP1A, OATP1B, OATP1C). Within the subfamilies, individual members are numbered according to the chronology of their identification and if there is already an ortholog known, they are given the same number. For example, the first SLCO identified, is rat OATP1A1 (encoded by the Slco1a1 gene). The second SLCO identified is the first human SLCO from the same subfamily and is called OATP1A2 (encoded by the SLCO1A2 gene). There are 11 human SLCOs/OATPs. SLCOs belong to the Major Facilitator Superfamily (MFS) of membrane transport proteins, which are thought to function through a single substrate binding site, alternating-access mechanism involving a rocker-switch type of movement.

                        10        20
                ....*....|....*....|...
gi 4504619  111 CVCKSR--YPVCGSDGTTYPSGC 131
Cdd:cd17336 316 CNCSDSsfSPVCGSDGITYFSPC 338