Summary: SH3 domain

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SH3 domain Edit Wikipedia article

SH3 domain

Ribbon diagram of the SH3 domain, alpha spectrin, from chicken (PDB accession code 1SHG), colored from blue (N-terminus) to red (C-terminus).

Identifiers

Symbol

SH3_1

Pfam clan

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

The SRC Homology 3 Domain (or SH3 domain) is a small protein domain of about 60 amino acids 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.^[1]^[2] It has also been identified in several other protein families such as: PI3 Kinase, Ras GTPase-activating protein, CDC24 and cdc25.^[3]^[4]^[5] 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.

Structure

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.^[6]

Peptide binding

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.

Many SH3-binding epitopes of proteins have a consensus sequence that can be represented as a regular expression or Short linear motif:

-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.

Proteins with SH3 domain

Adaptor proteins
CDC24
Cdc25
PI3 kinase
Phospholipase
Ras GTPase-activating protein
Vav proto-oncogene
GRB2
p54 S6 kinase 2 (S6K2)
SH3D21
C10orf76 (potentially)
STAC3
Some myosins
SHANK1,2,3
ARHGAP12
C8orf46
TANGO1
Integrase
Focal Adhesion Kinase (FAK, PTK2)
Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta)

References

^ Pawson T, Schlessingert J (July 1993). "SH2 and SH3 domains". Curr. Biol. 3 (7): 434–42. doi:10.1016/0960-9822(93)90350-W. PMID 15335710.
^ Mayer BJ (April 2001). "SH3 domains: complexity in moderation". J. Cell. Sci. 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 Lett. 307 (1): 55–61. doi:10.1016/0014-5793(92)80901-R. PMID 1639195.
^ Mayer BJ, Baltimore D (January 1993). "Signalling through SH2 and SH3 domains". Trends Cell Biol. 3 (1): 8–13. doi:10.1016/0962-8924(93)90194-6. PMID 14731533.
^ Pawson T (February 1995). "Protein modules and signalling networks". Nature 373 (6515): 573–80. doi:10.1038/373573a0. PMID 7531822.
^ Whisstock JC, Lesk AM (April 1999). "SH3 domains in prokaryotes". Trends Biochem. Sci. 24 (4): 132–3. doi:10.1016/s0968-0004(99)01366-3. PMID 10322416.

External links

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 page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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.

SH3 domain Provide feedback

SH3 (Src homology 3) domains are often indicative of a protein involved in signal transduction related to cytoskeletal organisation. First described in the Src cytoplasmic tyrosine kinase P12931. The structure is a partly opened beta barrel.

Literature references

Kami K, Takeya R, Sumimoto H, Kohda D; , EMBO J 2002;21:4268-4276.: Diverse recognition of non-PxxP peptide ligands by the SH3 domains from p67(phox), Grb2 and Pex13p. PUBMED:12169629 EPMC:12169629

Internal database links

SCOOP:	SH3_4 SH3_2 SH3_3 DUF3104 SH3_6 hSH3 SH3_9
Similarity to PfamA using HHSearch:	SH3_2 SH3_3 SH3_9

External database links

HOMSTRAD:	sh3
PRINTS:	PR00452
PROSITE:	PDOC50002
SCOP:	1shf

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-termini are packed in close proximity, indicating that they are independent structural modules.

Gene Ontology

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)

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan SH3 (CL0010), which has the following description:

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 [1]. 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 [1].

The clan contains the following 10 members:

hSH3 PhnA SH3_1 SH3_2 SH3_3 SH3_4 SH3_5 SH3_6 SH3_8 SH3_9

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.

Alignment types

We make a range of alignments for each Pfam-A family:

seed: the curated alignment from which the HMM for the family is built
full: the alignment generated by searching the sequence database using the HMM
RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
UniProt: alignment generated by searching the UniProtKB sequence database using the family HMM
NCBI: alignment generated by searching the NCBI sequence database using the family HMM
meta: alignment generated by searching the metagenomics sequence database using the family HMM

Viewing

You can see the alignments as HTML or in three different sequence viewers:

jalview: a Java applet developed at the University of Dundee. You will need Java installed before running jalview
HTML: an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
PP/Heatmap: an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.

Reformatting

You can download (or view in your browser) a text representation of a Pfam alignment in various formats:

Selex
Stockholm
FASTA
MSF

You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.

Downloading

You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.

View options

We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

	Seed (57)	Full (16621)	Representative proteomes				UniProt (31754)	NCBI (123277)	Meta (100)
	Seed (57)	Full (16621)	RP15 (3695)	RP35 (7042)	RP55 (11118)	RP75 (14584)	UniProt (31754)	NCBI (123277)	Meta (100)
Jalview	View	View	View	View	View	View	View	View	View
HTML	View
PP/heatmap	₁

¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (57)	Full (16621)	Representative proteomes				UniProt (31754)	NCBI (123277)	Meta (100)
	Seed (57)	Full (16621)	RP15 (3695)	RP35 (7042)	RP55 (11118)	RP75 (14584)	UniProt (31754)	NCBI (123277)	Meta (100)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

Download options

We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (57)	Full (16621)	Representative proteomes				UniProt (31754)	NCBI (123277)	Meta (100)
	Seed (57)	Full (16621)	RP15 (3695)	RP35 (7042)	RP55 (11118)	RP75 (14584)	UniProt (31754)	NCBI (123277)	Meta (100)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	Download	Download	Download	Download	Download	Download	Download	Download	Download

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

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.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation

Seed source:

Prosite

Previous IDs:

SH3;

Type:

Domain

Author:

Cerutti L, Sonnhammer ELL, Eddy SR, Finn RD

Number in seed:

57

Number in full:

16621

Average length of the domain:

47.20 aa

Average identity of full alignment:

28 %

Average coverage of the sequence by the domain:

7.00 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 17690987 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	22.9	22.9
Trusted cut-off	22.9	22.9
Noise cut-off	22.8	22.8

Model length:

48

Family (HMM) version:

26

Download:

download the raw HMM for this family

Species distribution

Sunburst
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Colour assignments

Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Selections

Align selected sequences to HMM

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.

How the sunburst is generated

The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.

In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:

superkingdom
kingdom
phylum
class
order
family
genus
species

Colouring and labels

Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.

As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.

Anomalies in the taxonomy tree

There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.

Missing taxonomic levels

Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.

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.

So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".

Sub-species

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.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

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.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Interactions

There are 25 interactions for this family. More...

SH2 Guanylate_kin P53 F-protein ITAM Spectrin Ank LIM DUF3513 SH2 PB1 SH3_1 Ank_2 F-protein ubiquitin p47_phox_C P53 SH3_9 Trypsin Pkinase_Tyr Spectrin SH3_2 SAMP Asp Cytochrom_B558a

Structures

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_1 domain has been found. There are 542 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 seqence.

Loading structure mapping...

v t e Protein domains

BAR BIR BZIP CARD C1 C2 DED ENTH FYVE HEAT Kringle LIM LRR NACHT PAS PDZ Pyrin PH PX SH2 SH3 SUN TRIO WD40 zinc finger

Family: SH3_1 (PF00018)

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