Identification of residues that control specific binding of the Shc phosphotyrosine-binding domain to phosphotyrosine sites

被引:96
作者
vanderGeer, P
Wiley, S
Gish, GD
Lai, VKM
Stephens, R
White, MF
Kaplan, D
Pawson, T
机构
[1] MT SINAI HOSP,SAMUEL LUNENFELD RES INST,PROGRAMME MOLEC BIOL & CANC,TORONTO,ON M5G 1X5,CANADA
[2] MT SINAI HOSP,SAMUEL LUNENFELD RES INST,PROT ENGN NETWORK CTR EXCELLENCE,TORONTO,ON M5G 1X5,CANADA
[3] NCI,FREDERICK CANC RES & DEV CTR,ABL BASIC RES PROGRAM,FREDERICK,MD 21702
[4] JOSLIN DIABET CTR,BOSTON,MA 02115
[5] BRIGHAM & WOMENS HOSP,DEPT MED,BOSTON,MA 02115
[6] HARVARD UNIV,SCH MED,BOSTON,MA 02115
关键词
tyrosine phosphorylation; signal transduction;
D O I
10.1073/pnas.93.3.963
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The She adaptor protein contains two phosphotyrosine [Tyr(P)]binding modules-an N-terminal Tyr(P) binding (PTB) domain and a C-terminal Src homology 2 (SH2) domain, We have compared the ability of the She PTB domain to bind the receptors for nerve growth factor and insulin, both of which contain juxtamembrane Asn-Pro-Xaa-Tyr(P) motifs implicated in PTB binding, The She PTB domain binds with high affinity to a phosphopeptide corresponding to the nerve growth factor receptor Tyr-490 autophosphorylation site, Analysis of individual residues within this motif indicates that the Asn at position -3 [with respect to Tyr(P)], in addition to Tyr(P), is critical for PTB binding, while the Pro at position -2 plays a less significant role. A hydrophobic amino acid 5 residues N-terminal to the Tyr(P) is also essential for high-affinity binding, In contrast, the She PTB domain does not bind stably to the Asn-Pro-Xaa-Tyr(P) site at Tyr-960 in the activated insulin receptor, which has a polar residue (Ser) at position -5. Substitution of this Ser at position -5 with Ile markedly increased binding of the insulin receptor Tyr-960 phosphopeptide to the PTB domain, These results suggest that while the She PTB domain recognizes a core sequence of Asn-Pro-Xaa-Tyr(P), its binding affinity is modulated by more N-terminal residues in the ligand, which therefore contribute to the specificity of PTB-receptor interactions, An analysis of residues in the She PTB domain required for binding to Tyr(P) sites identified a specific and evolutionarily conserved Arg (Arg-175) that is uniquely important for ligand binding and is potentially involved in Tyr(P) recognition.
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页码:963 / 968
页数:6
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