Editing SH3 domain

{{short description|Small protein domain found in some kinases and GTPases}}
{{Infobox protein family
| Symbol = SH3_1
| Name = SH3 domain
| image =1shg SH3 domain.png
| width =200
| caption =[[Ribbon diagram]] of the SH3 domain, alpha spectrin, from [[chicken]] (PDB accession code 1SHG), colored from blue (N-terminus) to red (C-terminus).
| Pfam= PF00018
| Pfam_clan= CL0010
| ECOD = 4.1.1
| InterPro= IPR001452
| SMART=  SM00326
| PROSITE = PS50002
| SuperFamily = SSF50044
| SCOP = 1shf
| TCDB =
| CDD = cd00174
| OPM family=
| OPM protein=
| PDB=
}}

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 [[Virus|viral]] [[Signal transducing adaptor protein|adaptor protein]] v-Crk. This domain is also present in the molecules of phospholipase and several cytoplasmic [[tyrosine kinase]]s such as [[Abl gene|Abl]] and [[Sarcoma inducing gene|Src]].<ref name="pmid15335710">{{cite journal | vauthors = Pawson T, Schlessingert J | title = SH2 and SH3 domains | journal = Current Biology | volume = 3 | issue = 7 | pages = 434–42 | date = July 1993 | pmid = 15335710 | doi = 10.1016/0960-9822(93)90350-W | s2cid = 53273571 }}</ref><ref name="pmid11256992">{{cite journal | vauthors = Mayer BJ | title = SH3 domains: complexity in moderation | journal = Journal of Cell Science | volume = 114 | issue = Pt 7 | pages = 1253–63 | date = April 2001 | doi = 10.1242/jcs.114.7.1253 | pmid = 11256992 }}</ref> It has also been identified in several other protein families such as: [[PI3 Kinase]], [[Ras superfamily|Ras]] [[RasGAP|GTPase-activating protein]], [[CDC24]] and [[cdc25]].<ref name="pmid1639195">{{cite journal | vauthors = Musacchio A, Gibson T, Lehto VP, Saraste M | title = SH3--an abundant protein domain in search of a function | journal = FEBS Letters | volume = 307 | issue = 1 | pages = 55–61 | date = July 1992 | pmid = 1639195 | doi = 10.1016/0014-5793(92)80901-R | s2cid = 8564342 | doi-access =  }}</ref><ref name="pmid14731533">{{cite journal | vauthors = Mayer BJ, Baltimore D | title = Signalling through SH2 and SH3 domains | journal = Trends in Cell Biology | volume = 3 | issue = 1 | pages = 8–13 | date = January 1993 | pmid = 14731533 | doi = 10.1016/0962-8924(93)90194-6 }}</ref><ref name="pmid7531822">{{cite journal | vauthors = Pawson T | title = Protein modules and signalling networks | journal = Nature | volume = 373 | issue = 6515 | pages = 573–80 | date = February 1995 | pmid = 7531822 | doi = 10.1038/373573a0 | s2cid = 4324726 }}</ref> 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]]<ref>{{cite journal | vauthors = Schlessinger J | title = SH2/SH3 signaling proteins | journal = Current Opinion in Genetics & Development | volume = 4 | issue = 1 | pages = 25–30 | date = February 1994 | pmid = 8193536 | doi = 10.1016/0959-437X(94)90087-6 }}</ref> and regulating the interactions of proteins involved in the cytoplasmic signaling.<ref>{{cite journal | vauthors = Koch CA, Anderson D, Moran MF, Ellis C, Pawson T | title = SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins | journal = Science | volume = 252 | issue = 5006 | pages = 668–74 | date = May 1991 | doi = 10.1126/science.1708916 | pmid = 1708916 }}</ref>

==Structure==
The SH3 domain has a characteristic [[beta-barrel]] fold that consists of five or six [[beta strand|β-strands]] arranged as two tightly packed [[anti-parallel β sheet]]s. The linker regions may contain short helices. The SH3-type fold is an ancient fold found in eukaryotes as well as prokaryotes.<ref name="pmid10322416">{{cite journal | vauthors = Whisstock JC, Lesk AM | title = SH3 domains in prokaryotes | journal = Trends in Biochemical Sciences | volume = 24 | issue = 4 | pages = 132–3 | date = April 1999 | pmid = 10322416 | doi = 10.1016/s0968-0004(99)01366-3 }}</ref>

==Peptide binding==
The classical SH3 domain is usually found in proteins that interact with other [[Protein|proteins]] and mediate assembly of specific protein complexes, typically via binding to [[proline]]-rich [[Peptide|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 [[hydrophobe|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 interactomes==
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.<ref name=":0">{{Cite journal|last1=Xin|first1=Xiaofeng|last2=Gfeller|first2=David|last3=Cheng|first3=Jackie|last4=Tonikian|first4=Raffi|last5=Sun|first5=Lin|last6=Guo|first6=Ailan|last7=Lopez|first7=Lianet|last8=Pavlenco|first8=Alevtina|last9=Akintobi|first9=Adenrele|date=2013-01-01|title=SH3 interactome conserves general function over specific form|journal=Molecular Systems Biology|volume=9|pages=652|doi=10.1038/msb.2013.9|issn=1744-4292|pmc=3658277|pmid=23549480}}</ref><ref>{{Cite journal|last1=Tonikian|first1=Raffi|last2=Xin|first2=Xiaofeng|last3=Toret|first3=Christopher P.|last4=Gfeller|first4=David|last5=Landgraf|first5=Christiane|last6=Panni|first6=Simona|last7=Paoluzi|first7=Serena|last8=Castagnoli|first8=Luisa|last9=Currell|first9=Bridget|date=2009-10-01|title=Bayesian modeling of the yeast SH3 domain interactome predicts spatiotemporal dynamics of endocytosis proteins|journal=PLOS Biology|volume=7|issue=10|pages=e1000218|doi=10.1371/journal.pbio.1000218|issn=1545-7885|pmc=2756588|pmid=19841731 |doi-access=free }}</ref> Nevertheless, orthologous SH3 domain-mediated interactions are highly rewired between worm and yeast.<ref name=":0" />

==Proteins with SH3 domain==
*[[Signal transducing adaptor protein]]s
*[[CDC24]]
*[[Cdc25]]
*[[Phosphoinositide 3-kinase|PI3 kinase]]
*[[Phospholipase]]
*[[RasGAP|Ras GTPase-activating protein]]
*[[Vav (protein)|Vav proto-oncogene]]
*[[GRB2]]
*[[Ribosomal s6 kinase|p54 S6 kinase 2 (S6K2)]]
*[[SH3D21]]
*[[ARMH3]] (potentially)
*[[STAC3]]
* Some [[myosins]]
* SH3 and multiple ankyrin repeat domains: [[SHANK1]], [[SHANK2]], [[SHANK3]]
*[[YAP1]]
*[[ARHGAP12]]
* vexin ([[VXN]])
*[[TANGO1]]
*[[Integrase]]
*[[PTK2|Focal Adhesion Kinase (FAK, PTK2)]]
*[[PTK2B|Proline-rich tyrosine kinase (Pyk2, CADTK, PTK2beta)]]
*[[TRIP10]] (cip4)

== See also ==
*[[Src homology 2 domain-containing]]
*[[Structural domain]]

== References ==
<references />

== External links ==
*{{ELM|LIG_SH3_1}}
*{{ELM|LIG_SH3_2}}
*{{ELM|LIG_SH3_3}}
*{{ELM|LIG_SH3_4}}
*{{ELM|LIG_SH3_5}} 
*{{ELM|TRG_PEX_1}}
* [http://nashlab.bsd.uchicago.edu/index.php?option=com_content&task=view&id=28&Itemid=29 Nash Lab Protein Interaction Domains in Signal Transduction - The SH3 domain]{{Dead link|date=August 2024 |bot=InternetArchiveBot |fix-attempted=yes }}
* [http://www.geneart.com/english/products-services/directed-evolution/sh3-library/index.html GENEART - Screen your protein against all human SH3 domains in a single phage display cycle] {{Webarchive|url=https://web.archive.org/web/20090707205309/http://www.geneart.com/english/products-services/directed-evolution/sh3-library/index.html |date=2009-07-07 }}

{{Protein domains}}

[[Category:Protein domains]]
[[Category:Protein superfamilies]]