Binding specificity and mutational analysis of the phosphotyrosine binding domain of the brain-specific adaptor protein ShcC

被引:17
作者
OBryan, JP
Martin, CB
Songyang, Z
Cantley, LC
Der, CJ
机构
[1] HARVARD UNIV, SCH MED, BOSTON, MA 02115 USA
[2] BETH ISRAEL HOSP, DEPT MED, BOSTON, MA 02115 USA
关键词
D O I
10.1074/jbc.271.20.11787
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
She proteins (hereafter referred to as ShcA) represent major substrates of tyrosine phosphorylation by a wide variety of growth factors and cytokines, We have recently described a novel ShcA-like protein, ShcC, which like ShcA contains an NH2-terminal phosphotyrosine binding domain (PTB), a central effector region (CH1) and a COOH-terminal Src homology 2 domain (SH2). Both the SH2 and PTB domains of ShcC bind a similar profile of proteins as the comparable regions of ShcA. In an effort to define the functional differences or similarities between ShcA and ShcC, we have further characterized the PTB domain of ShcC. Using a degenerate phosphopeptide library screen, we show that the PTB domain of ShcC preferentially binds the sequence His-hydrophobic-Asn/hydrophobic-Asn-Pro-Ser/Thr-Tyr(P). This sequence is similar to the binding site for the ShcA PTB domain, suggesting that these two proteins may have overlapping specificities. In addition, random mutagenesis of the ShcC PTB domain has identified several amino acids important for PTB function (Gly(32), Glu(63), Ala(136), Gly(139), and Asp(140)). Mutation of these amino acids dramatically reduces the affinity of the ShcC PTB domain for the activated epidermal growth factor receptor in vitro.
引用
收藏
页码:11787 / 11791
页数:5
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