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 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_SRC  LIG_SH2_STAP1  LIG_SH2_STAT3  LIG_SH2_STAT5  LIG_SH2_STAT6 
ELM Description:
Src-family Src Homology 2 (SH2) domains binding motif.
Pattern Probability: 0.0008729
Present in taxons: Bos taurus Cavia porcellus Gallus gallus Homo sapiens Mesocricetus auratus Metazoa Mus musculus Sus scrofa
Interaction Domain:
SH2 (PF00017) SH2 domain (Stochiometry: 1 : 1)
o See 24 Instances for LIG_SH2_SRC
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 18 selected references:

o 2 GO-Terms:

o 24 Instances for LIG_SH2_SRC
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
B7UM99 tir
474 477 AHQPEEHIYDEVAADPGYSV TP 10 Escherichia coli O127:H6 str. E2348/69
P97318 Dab1
198 201 EEDVEDPVYQYIVFEAGHEP TP 4 Mus musculus (House mouse)
324 327 HQEEEEPQYEEIPIYLELLP TP 2 Hamster polyomavirus
Q14118 DAG1
892 895 KGSRPKNMTPYRSPPPYVPP TP 4 Homo sapiens (Human)
Q60598 Cttn
421 424 DRPPSSPIYEDAAPFKAEPS TP 3 Mus musculus (House mouse)
P34152-3 Ptk2
397 400 VSVSETDDYAEIIDEEDTYT TP 5 Mus musculus (House mouse)
O60500 NPHS1
1176 1179 DMAFPGHLYDEVERTYPPSG TP 2 Homo sapiens (Human)
Q14511 NEDD9
629 632 SERSWMDDYDYVHLQGKEEF TP 2 Homo sapiens (Human)
Q05397 PTK2
397 400 VSVSETDDYAEIIDEEDTYT TP 1 Homo sapiens (Human)
Q60787 Lcp2
145 148 ALVDDAADYEPPPSNNEEAL TP 1 Mus musculus (House mouse)
581 584 SSDGHEYIYVDPMQLPYDST U 0 Homo sapiens (Human)
P12931 SRC
530 533 AFLEDYFTSTEPQYQPGENL TP 1 Homo sapiens (Human)
P56945 BCAR1
664 667 SEGGWMEDYDYVHLQGKEEF U 0 Homo sapiens (Human)
P56945 BCAR1
653 656 SQDSPDGQYENSEGGWMEDY U 0 Homo sapiens (Human)
Q90738 AFAP1
453 456 DPGALHYDYIDVEMTASVIQ U 0 Gallus gallus (Chicken)
Q90738 AFAP1
451 454 STDPGALHYDYIDVEMTASV U 0 Gallus gallus (Chicken)
Q90738 AFAP1
94 97 TSSLPEGYYEEAVPVSPGKA U 0 Gallus gallus (Chicken)
P49023 PXN
40 43 SYPTGNHTYQEIAVPPPVPP U 0 Homo sapiens (Human)
Q14289 PTK2B
402 405 SCSIESDIYAEIPDETLRRP U 0 Homo sapiens (Human)
P00533 EGFR
1125 1128 PAPSRDPHYQDPHSTAVGNP U 0 Homo sapiens (Human)
P00533 EGFR
1016 1019 DDVVDADEYLIPQQGFFSSP U 0 Homo sapiens (Human)
P08581 MET
1356 1359 HYVHVNATYVNVKCVAPYPS U 0 Homo sapiens (Human)
P08581 MET
1349 1352 FSTFIGEHYVHVNATYVNVK U 0 Homo sapiens (Human)
P06241 FYN
531 534 SFLEDYFTATEPQYQPGENL TP 0 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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