Summary: Variant SH3 domain
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SH3 domain Edit Wikipedia article
Ribbon diagram of the SH3 domain, alpha spectrin, from chicken (PDB accession code 1SHG), colored from blue (N-terminus) to red (C-terminus).
The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acid residues. Initially, SH3 was described as a conserved sequence in the viral adaptor protein v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src. It has also been identified in several other protein families such as: PI3 Kinase, Ras GTPase-activating protein, CDC24 and cdc25. SH3 domains are found in proteins of signaling pathways regulating the cytoskeleton, the Ras protein, and the Src kinase and many others. The SH3 proteins interact with adaptor proteins and tyrosine kinases. Interacting with tyrosine kinases SH3 proteins usually bind far away from the active site. Approximately 300 SH3 domains are found in proteins encoded in the human genome. In addition to that, the SH3 domain was responsible for controlling protein-protein interactions in the signal transduction pathways and regulating the interactions of proteins involved in the cytoplasmic signaling.
The SH3 domain has a characteristic beta-barrel fold that consists of five or six β-strands arranged as two tightly packed anti-parallel β sheets. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.
The classical SH3 domain is usually found in proteins that interact with other proteins and mediate assembly of specific protein complexes, typically via binding to proline-rich peptides in their respective binding partner. Classical SH3 domains are restricted in humans to intracellular proteins, although the small human MIA family of extracellular proteins also contain a domain with an SH3-like fold.
-X-P-p-X-P- 1 2 3 4 5
with 1 and 4 being aliphatic amino acids, 2 and 5 always and 3 sometimes being proline. The sequence binds to the hydrophobic pocket of the SH3 domain. More recently, SH3 domains that bind to a core consensus motif R-x-x-K have been described. Examples are the C-terminal SH3 domains of adaptor proteins like Grb2 and Mona (a.k.a. Gads, Grap2, Grf40, GrpL etc.). Other SH3 binding motifs have emerged and are still emerging in the course of various molecular studies, highlighting the versatility of this domain.
SH3 domain mediated protein-protein interaction networks, i.e., SH3 interactomes, revealed that worm SH3 interactome resembles the analogous yeast network because it is significantly enriched for proteins with roles in endocytosis. Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.
Proteins with SH3 domain
- Signal transducing adaptor proteins
- PI3 kinase
- Ras GTPase-activating protein
- Vav proto-oncogene
- p54 S6 kinase 2 (S6K2)
- C10orf76 (potentially)
- Some myosins
- Focal Adhesion Kinase (FAK, PTK2)
- Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta)
- TRIP10 (cip4)
- Pawson T, Schlessingert J (July 1993). "SH2 and SH3 domains". Current Biology. 3 (7): 434–42. PMID 15335710. doi:10.1016/0960-9822(93)90350-W.
- Mayer BJ (April 2001). "SH3 domains: complexity in moderation". Journal of Cell Science. 114 (Pt 7): 1253–63. PMID 11256992.
- Musacchio A, Gibson T, Lehto VP, Saraste M (July 1992). "SH3--an abundant protein domain in search of a function". FEBS Letters. 307 (1): 55–61. PMID 1639195. doi:10.1016/0014-5793(92)80901-R.
- Mayer BJ, Baltimore D (January 1993). "Signalling through SH2 and SH3 domains". Trends in Cell Biology. 3 (1): 8–13. PMID 14731533. doi:10.1016/0962-8924(93)90194-6.
- Pawson T (February 1995). "Protein modules and signalling networks". Nature. 373 (6515): 573–80. PMID 7531822. doi:10.1038/373573a0.
- Schlessinger J (February 1994). "SH2/SH3 signaling proteins". Current Opinion in Genetics & Development. 4 (1): 25–30. PMID 8193536. doi:10.1016/0959-437X(94)90087-6.
- Koch CA, Anderson D, Moran MF, Ellis C, Pawson T (May 1991). "SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins". Science. 252 (5006): 668–74. PMID 1708916.
- Whisstock JC, Lesk AM (April 1999). "SH3 domains in prokaryotes". Trends in Biochemical Sciences. 24 (4): 132–3. PMID 10322416. doi:10.1016/s0968-0004(99)01366-3.
- Xin, Xiaofeng; Gfeller, David; Cheng, Jackie; Tonikian, Raffi; Sun, Lin; Guo, Ailan; Lopez, Lianet; Pavlenco, Alevtina; Akintobi, Adenrele (2013-01-01). "SH3 interactome conserves general function over specific form". Molecular Systems Biology. 9: 652. ISSN 1744-4292. PMC . PMID 23549480. doi:10.1038/msb.2013.9.
- Tonikian, Raffi; Xin, Xiaofeng; Toret, Christopher P.; Gfeller, David; Landgraf, Christiane; Panni, Simona; Paoluzi, Serena; Castagnoli, Luisa; Currell, Bridget (2009-10-01). "Bayesian modeling of the yeast SH3 domain interactome predicts spatiotemporal dynamics of endocytosis proteins". PLOS Biology. 7 (10): e1000218. ISSN 1545-7885. PMC . PMID 19841731. doi:10.1371/journal.pbio.1000218.
- Eukaryotic Linear Motif resource motif class LIG_SH3_1
- Eukaryotic Linear Motif resource motif class LIG_SH3_2
- Eukaryotic Linear Motif resource motif class LIG_SH3_3
- Eukaryotic Linear Motif resource motif class LIG_SH3_4
- Eukaryotic Linear Motif resource motif class LIG_SH3_5
- Eukaryotic Linear Motif resource motif class TRG_PEX_1
- Nash Lab Protein Interaction Domains in Signal Transduction - The SH3 domain
- GENEART - Screen your protein against all human SH3 domains in a single phage display cycle
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Variant SH3 domain Provide feedback
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Internal database links
|SCOOP:||DUF4648 hSH3 SH3_1 SH3_10 SH3_2 SH3_3 SH3_4|
|Similarity to PfamA using HHSearch:||SH3_1 SH3_2 SH3_10|
This tab holds annotation information from the InterPro database.
InterPro entry IPR001452
SH3 (src Homology-3) domains are small protein modules containing approximately 50 amino acid residues [ PUBMED:15335710 , PUBMED:11256992 ]. They are found in a great variety of intracellular or membrane-associated proteins [ PUBMED:1639195 , PUBMED:14731533 , PUBMED:7531822 ] for example, in a variety of proteins with enzymatic activity, in adaptor proteins, such as fodrin and yeast actin binding protein ABP-1.
The SH3 domain has a characteristic fold which consists of five or six beta-strands arranged as two tightly packed anti-parallel beta sheets. The linker regions may contain short helices. The surface of the SH3-domain bears a flat, hydrophobic ligand-binding pocket which consists of three shallow grooves defined by conservative aromatic residues in which the ligand adopts an extended left-handed helical arrangement. The ligand binds with low affinity but this may be enhanced by multiple interactions. The region bound by the SH3 domain is in all cases proline-rich and contains PXXP as a core-conserved binding motif. The function of the SH3 domain is not well understood but they may mediate many diverse processes such as increasing local concentration of proteins, altering their subcellular location and mediating the assembly of large multiprotein complexes [ PUBMED:7953536 ].
The crystal structure of the SH3 domain of the cytoskeletal protein spectrin, and the solution structures of SH3 domains of phospholipase C (PLC-y) and phosphatidylinositol 3-kinase p85 alpha-subunit, have been determined [ PUBMED:1279434 , PUBMED:7684655 , PUBMED:7681365 ]. In spite of relatively limited sequence similarity, their overall structures are similar. The domains belong to the alpha+beta structural class, with 5 to 8 beta-strands forming 2 tightly-packed, anti-parallel beta-sheets arranged in a barrel-like structure, and intervening loops sometimes forming helices. Conserved aliphatic and aromatic residues form a hydrophobic core (A11, L23, A29, V34, W42, L52 and V59 in PLC-y [ PUBMED:7681365 ]) and a hydrophobic pocket on the molecular surface (L12, F13, W53 and P55 in PLC-y). The conserved core is believed to stabilise the fold, while the pocket is thought to serve as a binding site for target proteins. Conserved carboxylic amino acids located in the loops, on the periphery of the pocket (D14 and E22), may be involved in protein-protein interactions via proline-rich regions. The N- and C-terminal are packed in close proximity, indicating that they are independent structural modules.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||protein binding (GO:0005515)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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Src homology-3 (SH3) domains are comprised of about 60 amino acids, performing either an assembly or regulatory role. For example, SH3 domains in the Grb2 adaptor protein are essential for protein-protein interactions and signal transduction in the p21 Ras-dependent growth factor signaling pathway. Alternatively, SH3 performs a regulatory role in the Src family of tyrosine kinases. SH3 domains bind a variety of peptide ligands, many of which contain a PxxP motif. This PxxP motif is flanked by different specificity elements . Structures of SH3 domains, both free and ligand complexed, have provided insights into the mechanism of ligand recognition. The SH3 fold consists of two anti-parallel beta sheets that lie at right angles to each other. Within the fold, there are two variable loops, referred to as RT and n-Src loops. When SH3 binds to its ligand, the proline rich ligand adopts a PPII helix conformation, with the PPII helix structure recognised by a pair of grooves on the surface of the SH3 domain that bind turns of the helix. The SH3 grooves are formed by a series of nearly parallel, well-conserved aromatic residues .
The clan contains the following 37 members:CAP_GLY DUF150_C DUF1541 DUF1653 DUF3104 DUF3247 DUF3601 DUF4453 DUF4648 Gemin6 Gemin7 GW hSH3 IN_DBD_C KapB MLVIN_C Myosin_N NdhS SH3_1 SH3_10 SH3_11 SH3_12 SH3_13 SH3_14 SH3_15 SH3_16 SH3_17 SH3_18 SH3_19 SH3_2 SH3_3 SH3_4 SH3_5 SH3_6 SH3_9 SlpA YjdM
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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|Seed source:||Jackhmmer, JCSG:target_422527|
|Number in seed:||23|
|Number in full:||39471|
|Average length of the domain:||51.40 aa|
|Average identity of full alignment:||32 %|
|Average coverage of the sequence by the domain:||7.05 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the SH3_9 domain has been found. There are 193 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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