The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
Phosphotyrosine ligands bound by SH2 domains
Functional site description:
ELM Description:
NCK is a ubiquitously expressed adaptor protein that modulates actin cytoskeleton dynamics and contains three SH3 domains and one SH2 domain at its C-terminal end. The human NCK family has two members, NCK1 (Nckα) and NCK2 (Nckβ/GRB4). Though NCK1 and NCK2 exhibit some degree of partner specificity, they share the same mode of ligand binding (Frese,2006). The NCK SH2 domain belongs to the class IA family, containing an aromatic residue (Phe) at the βD5 position (Kaneko,2010). Phosphopeptide libraries show that NCK1/2 SH2 domains bind the (Y)[DEStav][^KRHgw][PVAtslme][denqstagpm] consensus motif in tyrosine-phosphorylated proteins, with the main preference being for Pro or Val in position +3 and acidic or polar residues in position +1 with respect to the pTyr (Songyang,1993, Huang,2008). Two mammalian pathogens, enteropathogenic Escherichia coli (EPEC) and vaccinia virus, exploit Nck as part of their infection strategy. The Tir protein of EPEC, the main causative agent of severe infant diarrhea binds NCK1 and NCK2 SH2 domains through a high-affinity pYDEV motif (Frese,2006). The phosphate group of Tyr is tightly bound in the conserved pTyr SH2 hydrophilic pocket. The other two positions important for binding are pY+3 and pY+1. In the NCK SH2 domain, the EF loop is positioned away from the BG loop, exposing the pY+3 binding pocket where the side chain of Val forms tight interactions. While Val is critical for the high-affinity interaction, other residues like Pro, Ala, and Ile are tolerated at pY+3 but cause a significant reduction in binding affinity. The pY+1 position strongly favours an Asp that makes a salt bridge with an Arg at the β D3 position, with Glu, Ser and Thr allowed. The residue at pY+2 is less important as it does not make direct side-chain interactions with the SH2 domain, but aromatic residues are not allowed. A large range of residues are tolerated at position pY+4 with the best binders being Ala, Thr, Ser, and Tyr. Position pY+6 favors negatively charged residues such as Asp and Glu.
Pattern Probability: 0.0008293
Present in taxon: Metazoa
Interaction Domain:
o See 17 Instances for LIG_SH2_NCK_1
o Abstract
o 6 selected references:

o 15 GO-Terms:

o 17 Instances for LIG_SH2_NCK_1
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
Q13094 LCP2
145 149 PVEDDADYEPPPSNDEEALQ TP 3 Homo sapiens (Human)
Q13094 LCP2
128 132 DGEDDGDYESPNEEEEAPVE TP 3 Homo sapiens (Human)
Q13094 LCP2
113 117 SSFEEDDYESPNDDQDGEDD TP 3 Homo sapiens (Human)
P17948 FLT1
1333 1337 ACCSPPPDYNSVVLYSTPPI TP 2 Homo sapiens (Human)
Q99704 DOK1
362 366 DPKEDPIYDEPEGLAPVPPQ TP 2 Homo sapiens (Human)
P68619 VACWR159
112 116 APSTEHIYDSVAGSTLLINN TP 3 Vaccinia virus WR
B7UM99 tir
474 478 HQPEEHIYDEVAADPGYSVI TP 6 Escherichia coli O127:H6 str. E2348/69
P14317 HCLS1
378 382 EPEPENDYEDVEEMDRHEQE TP 4 Homo sapiens (Human)
Q14247 CTTN
421 425 RLPSSPVYEDAASFKAELSY TP 4 Homo sapiens (Human)
280 284 PKPSNPIYNEPDEPIAFYAM TP 4 Homo sapiens (Human)
Q9Z2B5 Eif2ak3
561 565 QCQTESKYDSVSADVSDNSW TP 4 Mus musculus (House mouse)
P52799 EFNB2
304 308 DSVFCPHYEKVSGDYGHPVY TP 1 Homo sapiens (Human)
Q9QZS7-2 Nphs1
1218 1222 YEDPRGIYDQVAADMDAGEP TP 4 Mus musculus (House mouse)
Q9QZS7-2 Nphs1
1194 1198 PGVWGPLYDEVQMDPYDLRW TP 4 Mus musculus (House mouse)
Q9QZS7-2 Nphs1
1177 1181 MAFPGHLYDEVERVYGPPGV TP 4 Mus musculus (House mouse)
P98172 EFNB1
317 321 ENNYCPHYEKVSGDYGHPVY TP 1 Homo sapiens (Human)
1009 1013 LDTSSVLYTAVQPNEGDNDY TP 1 Homo sapiens (Human)
