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 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:
Class IC SH2 domains bind a pTyr motif with specificity for Asn at the pY+2 position. Peptide scanning experiments define two main preferences at the pY+1 position that include acidic or hydrophobic residues (Tinti,2013; Huang,2008). While Grb2/Grb7/Grap/Gads Sh2s bind to both types of motifs, Grb10/14 and TNS1/4 have a strong preference for acidic residues at pY+1. At pY+1, hydrophobic residues make Van der Waals interactions with W121, F108 and Q106 of the SH2 domain, while acidic residues extend further into the groove, making polar interactions with Q106 and N143. The Gads SH2 domain has a more selective pY+1 pocket which disfavours bulky or large aliphatic residues (Cho,2004).
The pTyr provides the basal affinity, binding into a highly conserved pocket through multiple stabilizing interactions. The binding mode is determined by the conformation of the EF and BG loops, which plug access to the pY+3 pocket in these SH2 domains forcing the ligand to adopt a closed Type I β-turn conformation that exposes the +2 Asn prominently for binding (Kaneko,2010; Rahuel,1996). The Asn residue H bonds with the backbone of residues K109 and L120 in the SH2 domain. Proline is excluded from position pY+1 as it would prevent the U-shaped turn conformation (Huang,2008; Liu,2010). More open or twisted turn motifs are present in AICD, CDC28 and ErbB2 (Das,2011; Inaba,2017; Ivancic,2003).
The peptide ligand is held in place by backbone H bonds of pY-1 and pY+1 to the SH2 domain, and by an intramolecular H bond between pY+3 and pTyr that stabilizes the turn. Val or Met at pY+3 can make weak hydrophobic interactions with the SH2 domain. Positive charge in pY+3, pY+4 and pY+5 provides specificity, preventing binding to Class 1C SH2s with a positive surface patch surrounding the pTyr pocket (Grb2) but favouring Sh2s with negatively charged surfaces (Grb7) (Fiddes,1998; Spuches,2007).
Grb7,10,14 and TNS1,4 have reduced specificity for N at +2 and can bind motifs not matched by the ELM pattern.
Pattern: (Y)([EDST]|[MLIVAFYHQW])N.
Pattern Probability: 0.0003175
Present in taxon: Metazoa
Interaction Domain:
SH2 (PF00017) SH2 domain (Stochiometry: 1 : 1)
PDB Structure: 1FYR
o See 35 Instances for LIG_SH2_GRB2like
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 18 selected references:

o 14 GO-Terms:

o 35 Instances for LIG_SH2_GRB2like
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P10721 KIT
KIT_HUMAN
936 939 ISESTNHIYSNLANCSPNRQ TP 2 Homo sapiens (Human)
2 
O43561-2 LAT
LAT_HUMAN
226 229 EAEEVEEEGAPDYENLQELN TP 2 Homo sapiens (Human)
1 
O43561-2 LAT
LAT_HUMAN
191 194 ASLDGSREYVNVSQELHPGA TP 2 Homo sapiens (Human)
1 
O43561-2 LAT
LAT_HUMAN
171 174 FSMESIDDYVNVPESGESAE TP 2 Homo sapiens (Human)
1 
Q15303 ERBB4
ERBB4_HUMAN
1242 1245 KKAFDNPDYWNHSLPPRSTL TP 1 Homo sapiens (Human)
1 
Q15303 ERBB4
ERBB4_HUMAN
1188 1191 LQALDNPEYHNASNGPPKAE TP 1 Homo sapiens (Human)
1 
P10230 UL46
TEG1_HHV11
633 636 EEIPWMRVYENVCVNTANAA TP 3 Herpes simplex virus (type 1 / strain 17)
1 
Q02858 Tek
TIE2_MOUSE
1100 1103 RMLEERKTYVNTTLYEKFTY TP 5 Mus musculus (House mouse)
2 
Q61526 Erbb3
ERBB3_MOUSE
1259 1262 TTPDEDYEYMNRRRGAGGSG TP 1 Mus musculus (House mouse)
1 
P04626 ERBB2
ERBB2_HUMAN
1139 1142 LTCSPQPEYVNQPDVRPQPP TP 3 Homo sapiens (Human)
1 
Q06124 PTPN11
PTN11_HUMAN
584 587 MREDSARVYENVGLMQQQKS TP 3 Homo sapiens (Human)
1 
P09619 PDGFRB
PGFRB_HUMAN
775 778 ESSNYMAPYDNYVPSAPERT TP 3 Homo sapiens (Human)
1 
P09619 PDGFRB
PGFRB_HUMAN
716 719 RRPPSAELYSNALPVGLPLP TP 4 Homo sapiens (Human)
1 
P02718 CHNRD
ACHD_TORCA
393 396 GYISKAQEYFNIKSRSELMF TP 5 Torpedo californica (Pacific electric ray)
P00533 EGFR
EGFR_HUMAN
1110 1113 AGSVQNPVYHNQPLNPAPSR TP 3 Homo sapiens (Human)
1 
P00533 EGFR
EGFR_HUMAN
1092 1095 DTFLPVPEYINQSVPKRPAG TP 3 Homo sapiens (Human)
1 
P29353-2 SHC1
SHC1_HUMAN
317 320 RELFDDPSYVNVQNLDKARQ TP 7 Homo sapiens (Human)
1 
P35568 IRS1
IRS1_HUMAN
896 899 PEPKSPGEYVNIEFGSDQSG TP 4 Homo sapiens (Human)
1 
P30203 CD6
CD6_HUMAN
629 632 SSTSSGEWYQNFQPPPQPPS TP 4 Homo sapiens (Human)
2 
P10747 CD28
CD28_HUMAN
191 194 RSRLLHSDYMNMTPRRPGPT TP 3 Homo sapiens (Human)
2 
P11274 BCR
BCR_HUMAN
177 180 GADAEKPFYVNVEFHHERGL TP 1 Homo sapiens (Human)
1 
P05067-4 APP
A4_HUMAN
682 685 LSKMQQNGYENPTYKFFEQM TP 3 Homo sapiens (Human)
1 
Q05397 PTK2
FAK1_HUMAN
925 928 LDRSNDKVYENVTGLVKAVI TP 0 Homo sapiens (Human)
P40223 Csf3r
CSF3R_MOUSE
788 791 GPTPSPKSYENIWFHSRPQE U 0 Mus musculus (House mouse)
Q14289 PTK2B
FAK2_HUMAN
881 884 LDRTDDLVYLNVMELVRAVL TP 1 Homo sapiens (Human)
O54957 Lat
LAT_MOUSE
175 178 FSVESCEDYVNVPESEESAE TP 1 Mus musculus (House mouse)
O54957 Lat
LAT_MOUSE
195 198 ASLDGSREYVNVSPEQQPVT TP 1 Mus musculus (House mouse)
O54957 Lat
LAT_MOUSE
235 238 EEEGVDGEEAPDYENLQELN TP 1 Mus musculus (House mouse)
P29353 SHC1
SHC1_HUMAN
349 352 EEEPPDHQYYNDFPGKEPPL TP 1 Homo sapiens (Human)
P29353 SHC1
SHC1_HUMAN
427 430 RELFDDPSYVNVQNLDKARQ TP 2 Homo sapiens (Human)
Q06124 PTPN11
PTN11_HUMAN
546 549 KSKRKGHEYTNIKYSLADQT TP 1 Homo sapiens (Human)
P35570 Irs1
IRS1_RAT
895 898 PEPKSPGEYVNIEFGSGQPG TP 2 Rattus norvegicus (Norway rat)
P05067 APP
A4_HUMAN
757 760 LSKMQQNGYENPTYKFFEQM TP 4 Homo sapiens (Human)
P08581 MET
MET_HUMAN
1356 1359 HYVHVNATYVNVKCVAPYPS TP 2 Homo sapiens (Human)
1 
P21860 ERBB3
ERBB3_HUMAN
1262 1265 TTPDEDYEYMNRQRDGGGPG TP 1 Homo sapiens (Human)
Please cite: The eukaryotic linear motif resource - 2018 update. (PMID:29136216)

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