Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRKWWKARNSRGQVAHVPHTIVTP 581
Cdd:cd11764     1 YVRVLYDFTARNSKELSVLKGEYLEVLDDSRQWWKVRNSRGQVGYVPHNILEP 53

Virilizer, N-terminal; VIR_N is the conserved N-terminus of the protein virilizer, necessary for male and female viability and required for the production of eggs capable of embryonic development.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220 384 PRDQWKGHVPPYHPIFMDGWSPEYPiPEDRDHDHLASLLNADKQKRDELPEQQNDPYYNHRDVDESHYSSD--YLEYEsR 461
Cdd:pfam15912 161 PRPEPRGPRTPELLPAHTGNVPGPP-PPDDDEEEDHYVPVTVGEVKEENCEHRSDYLEPVSPPERTSLPAEetYSEAG-R 238

                          90       100
                  ....*....|....*....|....*
gi 1387148220 462 EERGGNEYFDRNYGPSSelyGREER 486
Cdd:pfam15912 239 EERRGSREGERDEEDSD---VRSRE 260

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRKWWKARNSRGQVAHVPHTIVTP 581
Cdd:cd11764     1 YVRVLYDFTARNSKELSVLKGEYLEVLDDSRQWWKVRNSRGQVGYVPHNILEP 53

Phosphotyrosine-binding domain; The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (pfam00017) domain and a region similar to the tumour suppressor PTEN. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220  36 YMMEHLATFTVTKETGIVYPADGMRRLLQLEKSNGIWSQKMQLRLERNWVLIMDNETGAIMERFPASLIQeptaFTSRDP 115
Cdd:pfam08416   2 YRVEHLTTFELDSLTGLQAVEDAIRKLQLLDAQGRVWTQEMLLQVSDQGITLTDNETKEELESYPLDSIS----HCQAVL 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1387148220 116 ME-MYNNILVFtVADDSGSGQrAEMHIFQCQSVSAQDLVEDL 156
Cdd:pfam08416  78 NDgRYNSILAL-VCQEPGQSK-PDVHLFQCDELGAELIAEDI 117

Phosphotyrosine-binding domain, phosphotyrosine-interaction (PI) domain; PTB/PI domain structure similar to those of pleckstrin homology (PH) and IRS-1-like PTB domains.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220   39 EHLATFTVTKETGIVYPADGMRRLLQLEKSNGIWSQKMQLRLERNWVLIMDNETGAIMERFPASLIqeptAFTSRDPmeM 118
Cdd:smart00462   9 KYLGSVEVPEARGLQVVQEAIRKLRAAQGSEKKEPQKVILSISSRGVKLIDEDTKAVLHEHPLRRI----SFCAVGP--D 82

                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 1387148220  119 YNNILVFtVADDSGSgQRAEMHIFQCQSVsAQDLVEDLK 157
Cdd:smart00462  83 DLDVFGY-IARDPGS-SRFACHVFRCEKA-AEDIALAIG 118

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
                  ....*....|....*....|....*....|....*....|....
gi 1387148220 534 YPRTANNDKELTVVRGEYLEILDDS-RKWWKARNSRGQVAHVPH 576
Cdd:pfam00018   4 YDYTAQEPDELSFKKGDIIIVLEKSeDGWWKGRNKGGKEGLIPS 47

large tegument protein UL36; Provisional

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220  580 TPHNPATHSADNDVFNnPLYTSRYPRQGHGYNYEDSEIERTSTSPGPETTHR---THAIPPPAPADWVRKERLGKKDDIS 656
Cdd:PHA03247  2615 SPLPPDTHAPDPPPPS-PSPAANEPDPHPPPTVPPPERPRDDPAPGRVSRPRrarRLGRAAQASSPPQRPRRRAARPTVG 2693

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220  657 SYNGISISDSSRSSTSSIESISQSNGKLNTQQSIVEVHSPPrdiiLDVIPDKPALPAPAALTLPPELSASKSTPALPASE 736
Cdd:PHA03247  2694 SLTSLADPPPPPPTPEPAPHALVSATPLPPGPAAARQASPA----LPAAPAPPAVPAGPATPGGPARPARPPTTAGPPAP 2769

                          170       180       190
                   ....*....|....*....|....*....|....*.
gi 1387148220  737 SAPKLPTSKSAPTLFVLKSIPILSPLKSAPASPVPA 772
Cdd:PHA03247  2770 APPAAPAAGPPRRLTRPAVASLSESRESLPSPWDPA 2805

Src Homology 3 domain of Epidermal growth factor receptor kinase substrate 8 and similar proteins; This group is composed of Eps8 and Eps8-like proteins including Eps8-like 1-3, among others. These proteins contain N-terminal Phosphotyrosine-binding (PTB), central SH3, and C-terminal effector domains. Eps8 binds either Abi1 (also called E3b1) or Rab5 GTPase activating protein RN-tre through its SH3 domain. With Abi1 and Sos1, it becomes part of a trimeric complex that is required to activate Rac. Together with RN-tre, it inhibits the internalization of EGFR. The SH3 domains of Eps8 and similar proteins recognize peptides containing a PxxDY motif, instead of the classical PxxP motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRKWWKARNSRGQVAHVPHTIVTP 581
Cdd:cd11764     1 YVRVLYDFTARNSKELSVLKGEYLEVLDDSRQWWKVRNSRGQVGYVPHNILEP 53

Phosphotyrosine-binding domain; The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) in the protein tensin tends to be found at the C-terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (pfam00017) domain and a region similar to the tumour suppressor PTEN. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220  36 YMMEHLATFTVTKETGIVYPADGMRRLLQLEKSNGIWSQKMQLRLERNWVLIMDNETGAIMERFPASLIQeptaFTSRDP 115
Cdd:pfam08416   2 YRVEHLTTFELDSLTGLQAVEDAIRKLQLLDAQGRVWTQEMLLQVSDQGITLTDNETKEELESYPLDSIS----HCQAVL 77

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1387148220 116 ME-MYNNILVFtVADDSGSGQrAEMHIFQCQSVSAQDLVEDL 156
Cdd:pfam08416  78 NDgRYNSILAL-VCQEPGQSK-PDVHLFQCDELGAELIAEDI 117

Src Homology 3 domain of Tec-like Protein Tyrosine Kinases; The Tec (Tyrosine kinase expressed in hepatocellular carcinoma) subfamily is composed of Tec, Btk, Bmx (Etk), Itk (Tsk, Emt), Rlk (Txk), and similar proteins. They are cytoplasmic (or nonreceptor) tyr kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Most Tec subfamily members (except Rlk) also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, some members contain the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. Tec kinases are expressed mainly by haematopoietic cells, although Tec and Bmx are also found in endothelial cells. B-cells express Btk and Tec, while T-cells express Itk, Txk, and Tec. Collectively, Tec kinases are expressed in a variety of myeloid cells such as mast cells, platelets, macrophages, and dendritic cells. Each Tec kinase shows a distinct cell-type pattern of expression. The function of Tec kinases in lymphoid cells have been studied extensively. They play important roles in the development, differentiation, maturation, regulation, survival, and function of B-cells and T-cells. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRK-WWKARNSRGQVAHVPHTIVTP 581
Cdd:cd11768     1 IVVALYDFQPIEPGDLPLEKGEEYVVLDDSNEhWWRARDKNGNEGYIPSNYVTE 54

First Src Homology 3 domain of Nck adaptor proteins; Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4), which show partly overlapping functions but also bind distinct targets. Their SH3 domains are involved in recruiting downstream effector molecules, such as the N-WASP/Arp2/3 complex, which when activated induces actin polymerization that results in the production of pedestals, or protrusions of the plasma membrane. The first SH3 domain of Nck proteins preferentially binds the PxxDY sequence, which is present in the CD3e cytoplasmic tail. This binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRKWWKARNSRGQVAHVP 575
Cdd:cd11765     1 YVVAKYDYTAQGDQELSIKKNEKLTLLDDSKHWWKVQNSSNQTGYVP 47

Third Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The third SH3 domain of Nck appears to prefer ligands with a PxAPxR motif. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEIL---DDSRKWWKARNSRGQVAHVPHTIV 579
Cdd:cd11903     2 VVQTLYPFSSVTEEELNFEKGETMEVIekpENDPEWWKCKNSRGQVGLVPKNYV 55

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 1387148220  527 GKIVQVTYPRTANNDKELTVVRGEYLEILDDSRK-WWKARNSRGQVAHVPHTIVT 580
Cdd:smart00326   2 GPQVRALYDYTAQDPDELSFKKGDIITVLEKSDDgWWKGRLGRGKEGLFPSNYVE 56

Phosphotyrosine-binding (PTB) PH-like fold; PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to bind peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lack tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1387148220  40 HLATFTVTKETGIVYPADGMRRLLQLEKSNGIWSQKMQLRLERNWVLIMDNETGAIMERFPASLIqeptAFTSRDPmeMY 119
Cdd:cd00934     7 YLGSVEVGSSRGVDVVEEALKALAAALKSSKRKPGPVLLEVSSKGVKLLDLDTKELLLRHPLHRI----SYCGRDP--DN 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|
gi 1387148220 120 NNILVFTVADDSGSGQRaeMHIFQCQSVS-AQDLVEDLKM 158
Cdd:cd00934    81 PNVFAFIAGEEGGSGFR--CHVFQCEDEEeAEEILQAIGQ 118

First Src Homology 3 domain of Nck2 adaptor protein; Nck2 (also called Nckbeta or Growth factor receptor-bound protein 4, Grb4) plays a crucial role in connecting signaling pathways of tyrosine kinase receptors and important effectors in actin dynamics and cytoskeletal remodeling. It binds neuronal signaling proteins such as ephrinB and Disabled-1 (Dab-1) exclusively. Nck adaptor proteins regulate actin cytoskeleton dynamics by linking proline-rich effector molecules to protein tyrosine kinases and phosphorylated signaling intermediates. They contain three SH3 domains and a C-terminal SH2 domain. They function downstream of the PDGFbeta receptor and are involved in Rho GTPase signaling and actin dynamics. Vertebrates contain two Nck adaptor proteins: Nck1 (also called Nckalpha) and Nck2, which show partly overlapping functions but also bind distinct targets. The first SH3 domain of Nck2 binds the PxxDY sequence in the CD3e cytoplasmic tail; this binding inhibits phosphorylation by Src kinases, resulting in the downregulation of TCR surface expression. SH3 domains are protein interaction domains that usually bind to proline-rich ligands with moderate affinity and selectivity, preferentially a PxxP motif. 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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRKWWKARNSRGQVAHVPHTIV 579
Cdd:cd11899     5 IVIAKWDYTAQQDQELDIKKNERLWLLDDSKTWWRVRNAANRTGYVPSNYV 55

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 1387148220 529 IVQVTYPRTANNDKELTVVRGEYLEILDDSRK-WWKARNSRGQVAHVPHT 577
Cdd:cd00174     1 YARALYDYEAQDDDELSFKKGDIITVLEKDDDgWWEGELNGGREGLFPAN 50

Src Homology 3 domain of Sorting Nexin 9 and similar proteins; Sorting nexins (SNXs) are Phox homology (PX) domain containing proteins that are involved in regulating membrane traffic and protein sorting in the endosomal system. SNXs differ from each other in their lipid-binding specificity, subcellular localization and specific function in the endocytic pathway. This subfamily consists of SH3 domain containing SNXs including SNX9, SNX18, SNX33, and similar proteins. SNX9 is localized to plasma membrane endocytic sites and acts primarily in clathrin-mediated endocytosis, while SNX18 is localized to peripheral endosomal structures, and acts in a trafficking pathway that is clathrin-independent but relies on AP-1 and PACS1. 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 1387148220 530 VQVTYPRTANNDKELTVVRGEYLEIL--DDSRKWWKARNSRGQVAHVPHTIVTP 581
Cdd:cd11763     2 VRALYDFDSQPSGELSLRAGEVLTITrqDVGDGWLEGRNSRGEVGLFPSSYVEI 55

Src homology 3 domain of Signal Transducing Adaptor Molecule 2; STAM2, also called EAST (Epidermal growth factor receptor-associated protein with SH3 and TAM domain) or Hbp (Hrs binding protein), is part of the endosomal sorting complex required for transport (ESCRT-0). It plays a role in sorting mono-ubiquinated endosomal cargo for trafficking to the lysosome for degradation. It is also involved in the regulation of exocytosis. STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 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 1387148220 530 VQVTYPRTANNDKELTVVRGEYLEILDDS-RKWWKARNSRGqVAHVPHTIVT 580
Cdd:cd11963     4 VRALYDFEAVEDNELTFKHGEIIIVLDDSdANWWKGENHRG-VGLFPSNFVT 54

SAM domain of TFCP2 transcription factors; SAM (sterile alpha motif) domain of TFCP2 transcription factors is a putative protein-protein interaction domain. Proteins of this group have an N-terminal DNA-binding CP2 domain, a central predicted SAM domain and a C-terminal dimerization domain. They are involved in transcriptional regulation from early development to terminal differentiation. In particular, they regulate expression of erythroid cell-specific alpha-globin, fibrinogen, and sex-determining gene SRY as well as lens alpha-crystallin. TFCP2 regulators can interact with NF-E4 proteins forming heteromeric stage selector protein complex (SSP). This complex is able to bind stage selector element (SSE) and regulate embryonic globin expression in fetal-erythroid cells.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1387148220 873 TPWEVQTWLSAKGFSqKICKQLENTNGTELFNLSRRRLEQLCGLSEGSRL 922
Cdd:cd09589     1 TPQEAQQWLHRNRFS-TFSRLFTNFSGADLLKLTREDVIQICGPADGIRL 49

Src Homology 3 domain of C-terminal Src kinase; CSK is a cytoplasmic (or nonreceptor) tyr kinase containing the Src homology domains, SH3 and SH2, N-terminal to the catalytic tyr kinase domain. They negatively regulate the activity of Src kinases that are anchored to the plasma membrane. To inhibit Src kinases, CSK is translocated to the membrane via binding to specific transmembrane proteins, G-proteins, or adaptor proteins near the membrane. CSK catalyzes the tyr phosphorylation of the regulatory C-terminal tail of Src kinases, resulting in their inactivation. It is expressed in a wide variety of tissues and plays a role, as a regulator of Src, in cell proliferation, survival, and differentiation, and consequently, in cancer development and progression. In addition, CSK also shows Src-independent functions. It is a critical component in G-protein signaling, and plays a role in cytoskeletal reorganization and cell migration. 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 1387148220 538 ANNDKELTVVRGEYLEILDDSR--KWWKARNSRGQVAHVP 575
Cdd:cd11769    12 GASEEDLPFKKGDILTIVAVTKdpNWYKAKNKDGREGMIP 51

Src homology 3 domain of Signal Transducing Adaptor Molecules; STAMs were discovered as proteins that are highly phosphorylated following cytokine and growth factor stimulation. They function in cytokine signaling and surface receptor degradation, as well as regulate Golgi morphology. They associate with many proteins including Jak2 and Jak3 tyrosine kinases, Hrs, AMSH, and UBPY. STAM adaptor proteins contain VHS (Vps27, Hrs, STAM homology), ubiquitin interacting (UIM), and SH3 domains. There are two vertebrate STAMs, STAM1 and STAM2, which may be functionally redundant; vertebrate STAMs contain ITAM motifs. They are part of the endosomal sorting complex required for transport (ESCRT-0). STAM2 deficiency in mice did not cause any obvious abnormality, while STAM1 deficiency resulted in growth retardation. Loss of both STAM1 and STAM2 in mice proved lethal, indicating that STAMs are important for embryonic development. 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 1387148220 530 VQVTYPRTANNDKELTVVRGEYLEILDDSR-KWWKARNSRGQ 570
Cdd:cd11820     3 VRALYDFEAAEDNELTFKAGEIITVLDDSDpNWWKGSNHRGE 44

Src homology 3 domain of Lck Protein Tyrosine Kinase; Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cells and natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling. Src kinases 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). 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
                  ....*....|....*....|....*....|....*....|.
gi 1387148220 540 NDKELTVVRGEYLEILDDSRKWWKARNSR-GQVAHVPHTIV 579
Cdd:cd12005    12 HDGDLGFEKGEKLRILEQSGEWWKAQSLTtGQEGFIPFNFV 52

Fifth Src homology 3 domain (or SH3E) of Intersectin; Intersectins (ITSNs) are adaptor proteins that function in exo- and endocytosis, actin cytoskeletal reorganization, and signal transduction. They are essential for initiating clathrin-coated pit formation. They bind to many proteins through their multidomain structure and facilitate the assembly of multimeric complexes. Vertebrates contain two ITSN proteins, ITSN1 and ITSN2, which exist in alternatively spliced short and long isoforms. The short isoforms contain two Eps15 homology domains (EH1 and EH2), a coiled-coil region and five SH3 domains (SH3A-E), while the long isoforms, in addition, contain RhoGEF (also called Dbl-homologous or DH), Pleckstrin homology (PH) and C2 domains. ITSN1 and ITSN2 are both widely expressed, with variations depending on tissue type and stage of development. The fifth SH3 domain (or SH3E) of ITSN1 has been shown to bind many protein partners including SGIP1, Sos1, dynamin1/2, CIN85, c-Cbl, SHIP2, N-WASP, and synaptojanin-1, among others. 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 1387148220 534 YPRTANNDKELTVVRGEYLEILD-DSRKWWKARnSRGQVAHVPHTIVTP 581
Cdd:cd11840     6 FPYTAQNEDELSFQKGDIINVLSkDDPDWWRGE-LNGQTGLFPSNYVEP 53

SAM domain of LBP9 transcriptional factors; SAM (sterile alpha motif) domain of LBP9 (also known as TFCP2L1 or CRTR-1 (CP2-Related Transcriptional Repressor-1)) transcription factor is a putative protein-protein interaction domain. Proteins of this group have an N-terminal DNA-binding CP2 domain, a central predicted SAM domain and a C-terminal dimerization domain. They are involved in transcriptional regulation from early development to terminal differentiation. In particular, they are required for proper maturation of the dust (epithelial component of tubular organs) of kidney and salivary gland as well as for regulation of P450scc (the cholesterol side-chain cleavage enzyme, cytochrome) in human placenta.

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                  ....*....|....*....|....*....|....*....|....*..
gi 1387148220 876 EVQTWLSAKGFSQkICKQLENTNGTELFNLSRRRLEQLCGLSEGSRL 922
Cdd:cd09590     4 DAQQWLHRNRFSQ-FCRLFSSFSGADLLKMSRDDFIQICGPADGIRL 49

C-terminal Src homology 3 domain of Growth factor receptor-bound protein 2; GRB2 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. It is ubiquitously expressed in all tissues throughout development and is important in cell cycle progression, motility, morphogenesis, and angiogenesis. In lymphocytes, GRB2 is associated with antigen receptor signaling components. GRB2 contains an N-terminal SH3 domain, a central SH2 domain, and a C-terminal SH3 domain. The C-terminal SH3 domain of GRB2 binds to Gab2 (Grb2-associated binder 2) through epitopes containing RxxK motifs, as well as to the proline-rich C-terminus of FGRF2. 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.

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                  ....*....|....*....|....*....|....*....|....*....|...
gi 1387148220 530 VQVTYPRTANNDKELTVVRGEYLEILDDSR-KWWKARnSRGQVAHVPHTIVTP 581
Cdd:cd11949     2 VQALFDFDPQEDGELGFRRGDFIEVMDNSDpNWWKGA-CHGQTGMFPRNYVTP 53