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_SRC  LIG_SH2_STAP1  LIG_SH2_STAT3  LIG_SH2_STAT5  LIG_SH2_STAT6 
ELM Description:
STAP1, Signal Adaptor Protein 1 (also known as STAP-1, BRDG1) is an adaptor protein with an SH2 and a PH class of lipid-binding domain. It is associated with autosomal dominant hypercholesterolaemia (Fouchier,2014). STAP1 is expressed in lymphoid cells and is phosphorylated by the Tec TK, which participates in B cell antigen receptor signaling (Ohya,1999).
The STAP1 SH2 domain has been classified as a Class IIC SH2 domain together with the BKS, CBL, CBLB and CBLC domains which are unusual in having pY+4 as the strongest specificity determinant: SPOT arrays revealed that the strongest preference at +4 is for Leu or Ile (though Val and Phe are accepted) (Huang,2008).
The structure of STAP1 bound to NTAL (3MAZ) shows that residues N-terminal to the pTyr are not strongly involved in binding (Kaneko,2010). The pTyr sits in the conserved pTyr pocket, establishing a network of hydrogen bond and van der Waals interactions with pocket-forming residues Arg184, Arg203, Ser212 and Lys228. The peptide is further stabilized by backbone hydrogen bonds from the +1 position to SH2 pocket residues His226, Glu239, and Lys228, similar to what is found for other SH2 domains. The +1 position has a preference for acidic or polar residues (Huang,2008) and the side chains of residues +1, +2 and +3 point towards solvent. +4 hydrophobic residues enter a deep hydrophobic pentagonally shaped pocket suited to accommodate these large side chains, with polar Tyr or smaller Ala residues being less favored. The +3 pocket in STAP1 is plugged by the EF loop residue Leu240, and the only requirement for +3 is the exclusion of Gly, Pro, and Trp. The BKS SH2 domain also has a “plugged” +3 pocket and shares a similar specificity to STAP1 (Kaneko,2010, Tinti,2013). Other Class IIC SH2 domains such as CBL have a shallower hydrophobic groove that preferentially accommodates a Pro residue at +4 (Kaneko,2010), and are not included in the current motif definition.
Pattern: (Y)[DESTA][^GP][^GP][ILVFMWYA]
Pattern Probability: 0.0010263
Present in taxon: Metazoa
Interaction Domain:
SH2 (PF00017) SH2 domain (Stochiometry: 1 : 1)
o See 22 Instances for LIG_SH2_STAP1
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 3 selected references:

o 6 GO-Terms:

o 22 Instances for LIG_SH2_STAP1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
O60500 NPHS1
NPHN_HUMAN
1217 1221 YQDPRGIYDQVAGDLDTLEP TP 1 Homo sapiens (Human)
1 
P13942 COL11A2
COBA2_HUMAN
344 348 TDPPEGPYDYTYGYGDDYRE TP 1 Homo sapiens (Human)
1 
Q93073-1 SECISBP2L
SBP2L_HUMAN
874 878 SEVNEKEYETNWRNMVETSD TP 1 Homo sapiens (Human)
1 
O75106 AOC2
AOC2_HUMAN
465 469 SVSSVGNYDYIWDFVLYPNG FP 1 Homo sapiens (Human)
1 
Q86UK7 ZNF598
ZN598_HUMAN
159 163 QHLQIFTYERKWYSRKDLAR FP 1 Homo sapiens (Human)
1 
P31994 FCGR2B
FCG2B_HUMAN
292 296 GAENTITYSLLMHPDALEEP TP 1 Homo sapiens (Human)
1 
P07949-1 RET
RET_HUMAN
1096 1100 RYPNDSVYANWMLSPSAAKL TP 1 Homo sapiens (Human)
1 
Q9UIB8-3 CD84
SLAF5_HUMAN
262 266 AASKKTIYTYIMASRNTQPA FP 1 Homo sapiens (Human)
1 
P42224 STAT1
STAT1_HUMAN
22 26 LEQVHQLYDDSFPMEIRQYL FP 1 Homo sapiens (Human)
1 
Q8WUK0 PTPMT1
PTPM1_HUMAN
75 79 VITMNEEYETRFLCNSSQEW FP 1 Homo sapiens (Human)
1 
Q8WZ42 TTN
TITIN_HUMAN
23044 23048 GLIQGEEYSFRVSAQNEKGI FP 1 Homo sapiens (Human)
1 
P20273 CD22
CD22_HUMAN
822 826 PEDEGIHYSELIQFGVGERP TP 1 Homo sapiens (Human)
1 
P20273 CD22
CD22_HUMAN
807 811 HKRQVGDYENVIPDFPEDEG TP 1 Homo sapiens (Human)
1 
Q13114 TRAF3
TRAF3_HUMAN
482 486 FVIMRGEYDALLPWPFKQKV FP 1 Homo sapiens (Human)
1 
Q9UDY8 MALT1
MALT1_HUMAN
470 474 MCRKRNDYDDTIPILDALKV TP 1 Homo sapiens (Human)
1 
P14317 HCLS1
HCLS1_HUMAN
397 401 EDEPEGDYEEVLEPEDSSFS TP 1 Homo sapiens (Human)
1 
O75582 RPS6KA5
KS6A5_HUMAN
423 427 DSPFYQHYDLDLKDKPLGEG TP 1 Homo sapiens (Human)
1 
Q13191 CBLB
CBLB_HUMAN
802 806 LNRTPSDYDLLIPPLGEDAF TP 2 Homo sapiens (Human)
1 
Q6Q0C0 TRAF7
TRAF7_HUMAN
275 279 FIGNQDTYETHLETCRFEGL FP 2 Homo sapiens (Human)
1 
Q9UBC2 EPS15L1
EP15R_HUMAN
564 568 AHRSLEQYDQVLDGAHGASL TP 2 Homo sapiens (Human)
1 
Q8TF42 UBASH3B
UBS3B_HUMAN
546 550 KLVVSESYDTYISRSFQVTK FP 1 Homo sapiens (Human)
1 
Q9GZY6 LAT2
NTAL_HUMAN
136 140 EDDDANSYENVLICKQKTTE TP 6 Homo sapiens (Human)
1 
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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