LIG_SH2_SFK_CTail_3
Accession: | |
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Functional site class: | Phosphotyrosine ligands bound by SH2 domains |
Functional site description: | Src Homology 2 (SH2) domains are small modular domains found within a great number of proteins involved in different signalling pathways. They are able to bind specific motifs containing a phosphorylated tyrosine residue, propagating the signal downstream by promoting protein-protein interactions and/or modifying enzymatic activities. Different families of SH2 domains may have different binding specificity, which is usually determined by a few residues C-terminal with respect to the pY (positions +1 to +4). Non-phosphorylated peptides do not bind to the SH2 domains. Several different binding motifs are known, for example: pYEEI (Src-family SH2 domains), pY [IV].[VILP] (SH-PTP2, phospholipase C-gamma), pY.[N] (GRB2). The interaction between SH2 domains and their substrates is however dependent also on cooperative contacts of other surface regions. |
ELMs with same func. site: | LIG_SH2_CRK LIG_SH2_GRB2like LIG_SH2_NCK_1 LIG_SH2_PTP2 LIG_SH2_SFK_2 LIG_SH2_SFK_CTail_3 LIG_SH2_STAP1 LIG_SH2_STAT3 LIG_SH2_STAT5 LIG_SH2_STAT6 |
ELM Description: | SRC family kinase (SFK) activity is regulated by tyrosine phosphorylation at its C-terminal tail by c-SRC-specific kinase (CSK) (Lipsick,2019). Phosphorylation mimics the interaction of LIG_SH2_SFK_2 motifs present in SRC substrates and regulators creating an autoinhibited conformation that blocks the SH2 motif binding cleft. The C-tail motif (LIG_SH2_SFK_CTail_3) is present in all SFKs, with slight variations in the binding mode. Two motif patterns can be derived from crystal structures, mutagenesis and sequence conservation. The first motif pattern is shared by SRC, FYN, YRK, FGR and YES. Structures of the c-SRC 527(Y)QPGE531 motif (Xu,1997) reveal conserved interactions of pY527 at the pTyr binding pocket and a conserved backbone hydrogen bond between pY+1 and the SH2 domain. The Q side chain at pY+1 adopts a similar conformation to E in the pYEEI motif, packing against TyrβD5 and making conserved van der Waals interactions with LysβD3. Residues pY+2 and pY+3 retain flexibility with poor electron density or variable positioning in crystal structures. A negatively charged residue at pY+4 matches the charge preference of the pocket. The second motif is present in LCK, HCK, LYN and BLK. The LCK (Y)QxQP sequence presents conserved interactions for the pYQ module, and an additional interaction is made by Pro at pY+4, which packs into the top of the pY+3 binding pocket (Eck,1994). The C-terminal Pro exposes a carboxylate group that provides the negative charge preference at the motif C-terminus. Intramolecular tethering explains the tolerance for a sub-optimal motif. The low (30-50µM) binding affinity of C-tail motifs (Bradshaw,1998) may be required to allow activation by physiological ligands whose affinities range from low µM to low nM. The relevance of the C-tail motif is underscored by the v-SRC oncogene from Rous Sarcoma Virus (Sefton,1986), where the loss of the autoinhibitory C-tail creates a constitutively active kinase that promotes proliferation in the absence of mitogenic signalling. |
Pattern: | ((Y)QPG[ED])|((Y)Q.QP$) |
Pattern Probability: | 8.971e-09 |
Present in taxon: | Vertebrata |
Interaction Domain: |
SH2 domain (IPR000980)
The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps
(Stochiometry: 1 : 1)
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Abstract |
The Src Homology 2 (SH2) domain is a major protein interaction module that is central to tyrosine kinase signaling. Over 120 SH2 domains are predicted in the human genome (Liu,2011). Among SH2 domain-containing proteins are kinases, phosphatases adaptors, ubiquitin ligases, transcription factors, guanine nucleotide exchange factors. The many processes involving SH2 domains range from mitogenic signaling to T cell activation. Mutations identified in many SH2 domain-containing proteins as well as the SH2 domain itself are associated with human diseases ranging from cancers, diabetes, to immunodeficiencies. SH2 domains are phosphotyrosine recognition domains, often mediating transient interactions with target proteins. The binding affinity of an SH2 domain to a pTyr containing ligand is moderate, with the typical affinity range between 0.1 µМ to 10 µМ for equilibrium dissociation constant values (Kd) (Kaneko,2012). The structure of the SH2 domain consists of a central antiparallel β-sheet formed by three or four β strands flanked by two α helices. In the canonical mode of SH2 binding, regions on either side of the central β sheet are involved in ligand binding. The N-terminal region is most conserved and contains the pTyr binding pocket. The C-terminal half of the SH2 domain exhibits greater structural variability and provides a platform for accommodating different kinds of SH2-binding motifs. Three loops surround the peptide binding pocket and are important for specificity: Because these loops can be flexible, considerable variation in peptide binding can apply for any given SH2 domain. For the majority of experimentally solved SH2:peptide ligand complex structures, the bound pTyr peptide forms an extended conformation and binds perpendicularly to the central β strands of the SH2 domain. However motifs that form alternative conformations are also identified as in the case of the GRB2 SH2 domain binding motif (Nioche,2002) where the motif forms a β-turn upon binding. Grb2 is a good example of a bifunctional adaptor protein that brings proteins into close proximity, allowing signal transduction through proteins that can span different compartments. SPOT arrays provide an overview of different SH2 specificities (Huang,2008) although it is clear that they do not fully capture all the possible motifs for any given SH2. SH2s fall into groups with related specificities such as the GRB2-like set with a preference for YxN, the Src-like family with a preference for Y--# or the unique Stat3 YxxQ preference. SPOT arrays indicate that some SH2s might have quite poor specificity, for example PLCγ1_C and GRB7: These may be quite promiscuous. A large set of SH2 motif patterns has been made available, based on the SPOT arrays and other available data [Samano-Sanchez,2023]. Because of overlapping specificities amongst SH2 domains, it is unlikely to be clear which proteins bind to a new pTyr candidate SH2-binding motif. Therefore temporal and spatial colocalization should be evaluated and ultimately direct in-cell binding demonstrated as well as interaction affinities measured by in vitro binding assays. In addition, some motifs might be bound by multiple SH2s, for example as part of a sequential signaling process. |
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Structural elements that regulate pp59c-fyn catalytic activity,
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middle-T antigen.
Cheng SH, Espino PC, Marshall J, Harvey R, Merrill J, Smith AE
J Virol 1991 Jan; 65 (1), 170-9
PMID: 1985196
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From c-src to v-src, or the case of the missing C terminus.
Sefton BM, Hunter T
Cancer Surv 1986; 5 (2), 159-72
PMID: 2430701
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Structure of the regulatory domains of the Src-family tyrosine kinase Lck.
Eck MJ, Atwell SK, Shoelson SE, Harrison SC
Nature 1994 Apr 21; 368 (6473), 764-9
PMID: 7512222
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Three-dimensional structure of the tyrosine kinase c-Src.
Xu W, Harrison SC, Eck MJ
Nature 1997 Feb 13; 385 (6617), 595-602
PMID: 9024657
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Crystal structure of the Src family tyrosine kinase Hck.
Sicheri F, Moarefi I, Kuriyan J
Nature 1997 Feb 13; 385 (6617), 602-9
PMID: 9024658
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Probing the "two-pronged plug two-holed socket" model for the mechanism of binding of the Src SH2 domain to phosphotyrosyl peptides: a thermodynamic study.
Bradshaw JM, Grucza RA, Ladbury JE, Waksman G
Biochemistry 1998 Jun 23; 37 (25), 9083-90
PMID: 9636054
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Crystal structures of c-Src reveal features of its autoinhibitory
mechanism.
Xu W, Doshi A, Lei M, Eck MJ, Harrison SC
Mol Cell 1999 May; 3 (5), 629-38
PMID: 10360179
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Dynamically Coupled Residues within the SH2 Domain of FYN Are Key to Unlocking Its Activity.
Huculeci R, Cilia E, Lyczek A, Buts L, Houben K, Seeliger MA, van Nuland N, Lenaerts T
Structure 2016 Nov 01; 24 (11), 1947-1959
PMID: 27692963
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The Src module: an ancient scaffold in the evolution of cytoplasmic tyrosine kinases.
Shah NH, Amacher JF, Nocka LM, Kuriyan J
Crit Rev Biochem Mol Biol 2018 Oct; 53 (5), 535-563
PMID: 30183386
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A History of Cancer Research: Tyrosine Kinases.
Lipsick J
Cold Spring Harb Perspect Biol 2019 Feb 01; 11 (2), 0
PMID: 30709881
10 GO-Terms:
4 Instances for LIG_SH2_SFK_CTail_3
(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 |
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P08631 HCK HCK_HUMAN |
522 | 526 | IQSVLDDFYTATESQYQQQP | TP | 1 | Homo sapiens (Human) | |
P06239 LCK LCK_HUMAN |
505 | 509 | LRSVLEDFFTATEGQYQPQP | TP | 1 | Homo sapiens (Human) | |
P06241 FYN FYN_HUMAN |
531 | 535 | SFLEDYFTATEPQYQPGENL | TP | 1 | Homo sapiens (Human) | |
P12931 SRC SRC_HUMAN |
530 | 534 | AFLEDYFTSTEPQYQPGENL | TP | 5 | Homo sapiens (Human) |
Please cite:
The Eukaryotic Linear Motif resource: 2022 release.
(PMID:34718738)
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