The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Phosphotyrosine ligands bound by SH2 domains
Functional site description:
Src Homology 2 (SH2) domains recognize small motifs containing a phosphorylated Tyrosine residue. Additional specificity determinants are mainly found up to four positions after the pTyr. They are primarily found in metazoa and close unicellular relatives which have Receptor Tyrosine Kinases (RTKs) as well as soluble TKs such as Src and Abl. SH2 is the main binding domain for TK phosphorylation signalling events.
ELMs with same func. site: LIG_SH2_CRK  LIG_SH2_GRB2like  LIG_SH2_NCK_1  LIG_SH2_PTP2  LIG_SH2_SRC  LIG_SH2_STAP1  LIG_SH2_STAT3  LIG_SH2_STAT5  LIG_SH2_STAT6 
ELM Description:
YXXQ motif found in the cytoplasmic region of cytokine receptors that bind STAT3 SH2 domain; a cytokine receptor might contain more YXXQ motif in its cytoplasmic region.
Pattern: (Y)..Q
Pattern Probability: 0.0007975
Present in taxons: Homo sapiens Metazoa
Interaction Domain:
SH2 (PF00017) SH2 domain (Stochiometry: 1 : 1)
o See 9 Instances for LIG_SH2_STAT3
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.
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 6 selected references:

o 2 GO-Terms:

o 9 Instances for LIG_SH2_STAT3
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
72 75 NVNIQTSTYLPQNAATNLNS TP 2 Herpesvirus saimiri (strain 484-77)
P48356 Lepr
1138 1141 TSGENFVPYMPQFQTCSTHS U 0 Mus musculus (House mouse)
P40189 IL6ST
915 918 EGMPKSYLPQTVRQGGYMPQ U 0 Homo sapiens (Human)
P40189 IL6ST
905 908 TDEGMPKSYLPQTVRQGGYM U 0 Homo sapiens (Human)
P40189 IL6ST
814 817 DGILPRQQYFKQNCSQHESS U 0 Homo sapiens (Human)
P40189 IL6ST
767 770 YSTVVHSGYRHQVPSVQVFS U 0 Homo sapiens (Human)
P40223 Csf3r
728 731 SLPALVQAYVLQGDPREISN U 0 Mus musculus (House mouse)
P40238 MPL
631 634 CCTTHIANHSYLPLSYWQQP U 0 Homo sapiens (Human)
Q99062 CSF3R
727 730 GLPTLVQTYVLQGDPRAVST TP 1 Homo sapiens (Human)
Please cite: ELM — the eukaryotic linear motif resource in 2020. (PMID:31680160)

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