The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Accession:
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:
STAT5 Src Homology 2 (SH2) domain binding motif. This is one of the most promiscuous motifs in ELM. It will match to approximately every third Tyr residue. Therefore the predictive power is very weak.
Pattern: (Y)[VLTFIC]..
Pattern Probability: 0.0032959
Present in taxons: Homo sapiens Metazoa
Interaction Domain:
SH2 (PF00017) SH2 domain (Stochiometry: 1 : 1)
o See 19 Instances for LIG_SH2_STAT5
o 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.
o 5 selected references:

o 2 GO-Terms:

o 19 Instances for LIG_SH2_STAT5
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q13480-2 GAB1
GAB1_HUMAN
619 622 DSHDSEENYVPMNPNLSSED TP 5 Homo sapiens (Human)
1 
Q13480-2 GAB1
GAB1_HUMAN
472 475 TEPIQEANYVPMTPGTFDFS TP 5 Homo sapiens (Human)
1 
1 
Q13480-2 GAB1
GAB1_HUMAN
447 450 SSEELDENYVPMNPNSPPRQ TP 5 Homo sapiens (Human)
1 
1 
O43561-2 LAT
LAT_HUMAN
132 135 EDDYHNPGYLVVLPDSTPAT TP 5 Homo sapiens (Human)
Q15303 ERBB4
ERBB4_HUMAN
1056 1059 IGHSPPPAYTPMSGNQFVYR TP 4 Homo sapiens (Human)
1 
P09793 Ctla4
CTLA4_MOUSE
201 204 RSPLTTGVYVKMPPTEPECE TP 2 Mus musculus (House mouse)
1 
P06213 INSR
INSR_HUMAN
1361 1364 RSYEEHIPYTHMNGGKKNGR TP 2 Homo sapiens (Human)
1 
P09619 PDGFRB
PGFRB_HUMAN
751 754 MSKDESVDYVPMLDMKGDVK U 0 Homo sapiens (Human)
Q01113 IL9R
IL9R_HUMAN
407 410 EWRVQTLAYLPQEDWAPTSL U 0 Homo sapiens (Human)
P16871 IL7R
IL7RA_HUMAN
449 452 SLGSNQEEAYVTMSSFYQNQ U 0 Homo sapiens (Human)
P14784 IL2RB
IL2RB_HUMAN
418 421 PLSGEDDAYCTFPSRDDLLL U 0 Homo sapiens (Human)
P32927 CSF2RB
IL3RB_HUMAN
766 769 PVKSGFEGYVELPPIEGRSP U 1 Homo sapiens (Human)
P32927 CSF2RB
IL3RB_HUMAN
628 631 SPPPGSLEYLCLPAGGQVQL U 1 Homo sapiens (Human)
P16471 PRLR
PRLR_HUMAN
342 345 PSQGMKPTYLDPDTDSGRGS U 1 Homo sapiens (Human)
1 
P10912 GHR
GHR_HUMAN
534 537 ENFLMDNAYFCEADAKKCIP U 1 Homo sapiens (Human)
P10912 GHR
GHR_HUMAN
566 569 PSLNQEDIYITTESLTTAAG U 1 Homo sapiens (Human)
P10912 GHR
GHR_HUMAN
627 630 KEFLSSCGYVSTDQLNKIMP U 1 Homo sapiens (Human)
P19235 EPOR
EPOR_HUMAN
368 371 GSEHAQDTYLVLDKWLLPRN U 0 Homo sapiens (Human)
P19235 EPOR
EPOR_HUMAN
426 429 GASAASFEYTILDPSSQLLR U 0 Homo sapiens (Human)
Please cite: ELM-the Eukaryotic Linear Motif resource-2024 update. (PMID:37962385)

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