LIG_SH3_1
Accession: | |
---|---|
Functional site class: | SH3 domain ligands |
Functional site description: | The SH3 domain is one of the best characterized protein domains. SH3 domains are involved in a wide-range of important cellular processes including intracellular signaling, cytoskeletal rearrangements and cell movement, cell growth and immune responses. They bind to proline-rich sequences with moderate selectivity. Early studies identified “PxxP” as a core conserved sequence motif for SH3 binding. These motifs are referred to as canonical binders, among which class I and class II ligands are distinguished based on their orientation. Since then, SH3 domains recognizing partners with multiple atypical SH3 binding motifs have also been described. |
ELMs with same func. site: | LIG_SH3_1 LIG_SH3_2 LIG_SH3_3 LIG_SH3_4 LIG_SH3_PxRPPK_7 LIG_SH3_PxxDY_5 LIG_SH3_PxxPPRxxK_8 LIG_SH3_PxxxRxxKP_6 |
ELM Description: | This is the motif recognized by class I SH3 domains |
Pattern: | [RKY]..P..P |
Pattern Probability: | 0.0012370 |
Present in taxons: | Bos taurus Gallus gallus Homo sapiens Mus musculus Opisthokonta Rattus norvegicus Saccharomyces cerevisiae |
Interaction Domain: |
SH3_1 (PF00018)
SH3 domain
(Stochiometry: 1 : 1)
|
Abstract |
SH3 (SRC Homology 3) domains constitute one of the largest protein domain families with over 300 representatives in the human proteome and 30 in the yeast proteome. SH3 domains are protein recognition modules that typically function in the assembly of signalosomes and signal transduction (Zarrinpar,2003) in signaling pathways, such as cell growth regulation, endocytosis and remodeling of the cytoskeleton. They are small protein interaction modules consisting of only 60 amino acids. At the secondary structure level, the domain displays a beta-sandwich arrangement of five beta-sheets, 3 loops and a short 310 helix (Saksela,2012). The classical SH3 ligand binding site is made up by two hydrophobic pockets and a negatively charged one usually called the specificity pocket, formed by the RT and the n-Src loops. SH3 domains generally recognise proline-rich motifs forming poly-proline type helices (PPII helixes) when bound to the SH3 (Aitio,2008). Most of the known and well-studied ligands of SH3 domains have the “PxxP” core motif. The ligands that contain the “PxxP” minimal sequence are now referred to as canonical or typical SH3 binding motifs. Based on the extensive searches for SH3 binding motifs, a classification system was established where Class I (LIG_SH3_1) and Class II (LIG_SH3_2) ligands were distinguished (Fernandez-Ballester,2004). Because of the pseudo-symmetrical nature of the PPII helix, the PXXP-binding site can recognize peptides in both orientations by using two different binding modes. In both cases the prolines make contact with the two hydrophobic pockets, but the orientation of the peptide will be determined by the position of the charged residue binding to the specificity pocket; the motif description is “(R/K)xxPxxP” for class I and “PxxPx(R/K)” for class II (Aitio,2008). A key conserved surface Trp residue in the SH3 binding pocket is known to adopt two different orientations that, in turn, determine the type of ligand (I or II) specifically recognized by the domain. Interestingly, some of the SH3 domains are capable of binding ligands both in Class I and Class II orientation (Fernandez-Ballester,2004). Interestingly, motif binding by at least a subset of SH3 domains seems to be regulated by receptor tyrosine kinases (RTKs) through phosphorylation of a conserved C-terminal Tyr residue within the domain that disturbs motif binding and thus leads to the collapse of the associated signaling networks (Dionne,2018). The canonical Class I and II motifs are recognized by diverse SH3 domains. However, a large-scale study on human SH3 domains showed that almost half of the investigated domains exhibit atypical binding specificities with no “PxxP” core (Teyra,2017). The hitherto identified atypical SH3 motifs include the “PxxDY” (LIG_SH3_PxxDY_5) (Li,2005; Kaneko,2008; Saksela,2012), different “RxxK-type” motifs (LIG_SH3_PxxxRxxKP_6; LIG_SH3_PxRPPK_7; LIG_SH3_PxxPPRxxK_8) (Liu,2003; Lewitzky,2001; Harkiolaki,2009; Lewitzky,2004), Px[PA]xPR (LIG_SH3_CIN85_PxpxPR_1) (Kurakin,2003; Rouka,2015), and “RKxxYxxY” (Kang,2000). These atypical recognition specificities are usually associated with only a specific subset of the SH3-containing proteins, which often belong to specific processes/pathways. “PxxDY'' motif binding has only been identified for a relatively few SH3 domain-containing proteins, including Nck1 (P16333) and Eps8L1 (Q8TE68). Nck1 is an adaptor protein functioning in signal transduction between diverse membrane receptors and the cytoskeleton (Li,2001). During the activation of T-cell receptors (TCRs), Nck1 binds to the “PxxDY'' motif of the CD3ε subunit (32317279). In a phage display screening of 296 human SH3 domains only the Nck1, Nck2, Eps8, Eps8L1, Eps8L3 and Eps8L2 proteins were identified as binders of the motif in Cd3ε, indicating that it is highly specific (Kesti,2007). Besides CD3ε, e3b1/abi-1 and US6NL were also demonstrated to have a functional “PxxDY” motif that binds to the SH3 of Eps8 (Mongiovi,1999). Interestingly, two E.coli effector proteins, namely NleH1 and NleH2, have been identified as Eps8 binders. During infection, probably due to being bound by NleH1 and NleH2, Eps8 shows an altered localization pattern within the cytoplasm that might compromise the formation of new microvilli (Pollock,2022). RxxK-type SH3-binding motifs are specifically recognized by the second (C-terminal) SH3 domains of GRB2 (P62993) and GRAP2 (also called GADS (O75791)) (Liu,2003; Lewitzky,2001; Harkiolaki,2009; Lewitzky,2004), and the two STAM proteins, STAM1 (Q92783) and STAM2 (O75886) have also been described to bind certain RxxK motifs (Kato,2000). RxxK motif-mediated interactions are typically involved in the signaling of T-cell and B-cell receptors, as well as receptor tyrosine kinases. The RxxK motifs are highly versatile: there is a canonical version “PxxxRxxKP” (LIG_SH3_PxxxRxxKP_6) and some variants where the RxxK is preceded by a PxxP motif in an overlapping “PxRPxK” (LIG_SH3_PxRPPK_7)(Harkiolaki,2009) or non-overlapping “PxxPxRxxK” arrangement (LIG_SH3_PxxPPRxxK_8; Lewitzky,2004). There is also a variant described where the R and K residues are placed further apart “RxxxxK” (Harkiolaki,2009). There is at least one available structure for all these variants, therefore the differences in secondary structures adopted in the bound peptides as well as in the contacts established with the SH3 pockets/residues are well-understood (Harkiolaki,2009). Most known RxxK motif-containing proteins, such as LCP2/SLP-76, GAB1, 2 and 3, B-cell linker protein (BLNK), STAM-binding protein and Ubiquitin carboxyl-terminal hydrolase 8 (mUBPY) employ the canonical RxxK for SH3 binding. Some proteins, such as GABs, employ more than one RxxK type, while, for instance, MAP4K1/HPK1 employs the combined motif “PxxPxRxxK” for binding to the C-terminal SH3 of GADS (Lewitzky,2004). |
-
Identification of a protein that binds to the SH3 region of Abl and is
similar to Bcr and GAP-rho.
Cicchetti P, Mayer BJ, Thiel G, Baltimore D
Science 1992 Aug 7; 257 (5071), 803-6
PMID: 1379745
-
Association of p62, a multifunctional SH2- and SH3-domain-binding protein,
with src family tyrosine kinases, Grb2, and phospholipase C gamma-1.
Richard S, Yu D, Blumer KJ, Hausladen D, Olszowy MW, Connelly PA, Shaw AS
Mol Cell Biol 1995 Jan; 15 (1), 186-97
PMID: 7799925
-
Identification of two SH3-binding motifs in the regulatory subunit of
phosphatidylinositol 3-kinase.
Kapeller R, Prasad KV, Janssen O, Hou W, Schaffhausen BS, Rudd CE, Cantley LC
J Biol Chem 1994 Jan 21; 269 (3), 1927-33
PMID: 8294442
-
Identification of a ten-amino acid proline-rich SH3 binding site.
Ren R, Mayer BJ, Cicchetti P, Baltimore D
Science 1993 Feb 19; 259 (5098), 1157-61
PMID: 8438166
-
Specificity of p47phox SH3 domain interactions in NADPH oxidase assembly
and activation.
de Mendez I, Homayounpour N, Leto TL
Mol Cell Biol 1997 Apr; 17 (4), 2177-85
PMID: 9121467
-
Regulation of Rad51 function by c-Abl in response to DNA damage.
Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Kharbanda S, Wang R, Sung P, Shinohara A, Weichselbaum R, Kufe D
J Biol Chem 1998 Feb 13; 273 (7), 3799-802
PMID: 9461559
-
Tau interacts with src-family non-receptor tyrosine kinases.
Lee G, Newman ST, Gard DL, Band H, Panchamoorthy G
J Cell Sci 1998 Nov; 111, 3167-77
PMID: 9763511
-
ASAP1, a phospholipid-dependent arf GTPase-activating protein that
associates with and is phosphorylated by Src.
Brown MT, Andrade J, Radhakrishna H, Donaldson JG, Cooper JA, Randazzo PA
Mol Cell Biol 1998 Dec; 18 (12), 7038-51
PMID: 9819391
-
p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA
damage.
Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY, Lu H, Kharbanda S, Weichselbaum R, Kufe D
Nature 1999 Jun 24; 399 (6738), 814-7
PMID: 10391251
-
Evidence for SH3 domain directed binding and phosphorylation of Sam68 by
Src.
Shen Z, Batzer A, Koehler JA, Polakis P, Schlessinger J, Lydon NB, Moran MF
Oncogene 1999 Aug 19; 18 (33), 4647-53
PMID: 10467411
-
A role for myosin-I in actin assembly through interactions with Vrp1p,
Bee1p, and the Arp2/3 complex.
Evangelista M, Klebl BM, Tong AH, Webb BA, Leeuw T, Leberer E, Whiteway M, Thomas DY, Boone C
J Cell Biol 2000 Jan 24; 148 (2), 353-62
PMID: 10648568
-
The importance of being proline: the interaction of proline-rich motifs in
signaling proteins with their cognate domains.
Kay BK, Williamson MP, Sudol M
FASEB J 2000 Feb; 14 (2), 231-41
PMID: 10657980
-
Scar/WAVE-1, a Wiskott-Aldrich syndrome protein, assembles an
actin-associated multi-kinase scaffold.
Westphal RS, Soderling SH, Alto NM, Langeberg LK, Scott JD
EMBO J 2000 Sep 1; 19 (17), 4589-600
PMID: 10970852
-
Meltrin alpha cytoplasmic domain interacts with SH3 domains of Src and
Grb2 and is phosphorylated by v-Src.
Suzuki A, Kadota N, Hara T, Nakagami Y, Izumi T, Takenawa T, Sabe H, Endo T
Oncogene 2000 Nov 30; 19 (51), 5842-50
PMID: 11127814
-
Identification and kinetic analysis of the interaction between Nck-2 and
DOCK180.
Tu Y, Kucik DF, Wu C
FEBS Lett 2001 Mar 2; 491 (3), 193-9
PMID: 11240126
-
SH3 domains: complexity in moderation.
Mayer BJ
J Cell Sci 2001 Apr; 114, 1253-63
PMID: 11256992
-
Processive phosphorylation of p130Cas by Src depends on SH3-polyproline
interactions.
Pellicena P, Miller WT
J Biol Chem 2001 Jul 27; 276 (30), 28190-6
PMID: 11389136
-
Measles virus envelope glycoproteins hetero-oligomerize in the endoplasmic
reticulum.
Plemper RK, Hammond AL, Cattaneo R
J Biol Chem 2001 Nov 23; 276 (47), 44239-46
PMID: 11535597
-
Binding of Fyn to MAP-2c through an SH3 binding domain. Regulation of the
interaction by ERK2.
Zamora-Leon SP, Lee G, Davies P, Shafit-Zagardo B
J Biol Chem 2001 Oct 26; 276 (43), 39950-8
PMID: 11546790
-
Both proline-rich sequences in the TH region of Bruton's tyrosine kinase
stabilize intermolecular interactions with the SH3 domain.
Hansson H, Smith CI, Hard T
FEBS Lett 2001 Nov 9; 508 (1), 11-5
PMID: 11707259
10 GO-Terms:
8 Instances for LIG_SH3_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, Name | Start | End | Subsequence | Logic | #Ev. | Organism | Notes |
---|---|---|---|---|---|---|---|
B7UM88 espF B7UM88_ECO27 |
169 | 175 | VSFKPTRQAPPPPTSGQASG | TP | 7 | Escherichia coli O127:H6 str. E2348/69 | |
B7UM88 espF B7UM88_ECO27 |
122 | 128 | VNFKPTRPAPPPPTSGQASG | TP | 9 | Escherichia coli O127:H6 str. E2348/69 | |
B7UM88 espF B7UM88_ECO27 |
75 | 81 | TSFTPSRPAPPPPTSGQASG | TP | 9 | Escherichia coli O127:H6 str. E2348/69 | |
Q06609 RAD51 RAD51_HUMAN |
315 | 321 | TRICKIYDSPCLPEAEAMFA | TP | 3 | Homo sapiens (Human) | |
P10636 MAPT TAU_HUMAN |
547 | 553 | KKVAVVRTPPKSPSSAKSRL | TP | 1 | Homo sapiens (Human) | |
Q06187 BTK BTK_HUMAN |
200 | 206 | EDQILKKPLPPEPAAAPVST | TP | 1 | Homo sapiens (Human) | |
Q06187 BTK BTK_HUMAN |
186 | 192 | SHRKTKKPLPPTPEEDQILK | TP | 1 | Homo sapiens (Human) | |
P27986 PIK3R1 P85A_HUMAN |
88 | 94 | ISPPTPKPRPPRPLPVAPGS | TP | 2 | Homo sapiens (Human) |
Please cite:
ELM-the Eukaryotic Linear Motif resource-2024 update.
(PMID:37962385)
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement
ELM data can be downloaded & distributed for non-commercial use according to the ELM Software License Agreement