A novel phosphotyrosine motif with a critical amino acid at position-2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1
A novel phosphotyrosine motif with a critical amino acid at position-2 for the SH2 domain-mediated activation of the tyrosine phosphatase SHP-1
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DOI：
10.1074/jbc.272.20.13066
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发表时间：
1997-05-16
影响因子：
4.8
通讯作者：
Long, EO
中科院分区：
文献类型：
--
作者：
Burshtyn, DN;Yang, WT;Long, EO
SHP-1是一种与抑制造血细胞激活途径相关的蛋白酪氨酸磷酸酶，其催化活性受其两个SH2(Src Homology 2)结构域的调节；与SH2结构域结合的磷酸酪氨酸肽激活SHP-1，共有的序列(I/V)XYXX(L/V)存在于几个与SHP-1的第二个SH2结构域相互作用的淋巴细胞受体的细胞质尾部，在其中几个受体中，存在两到三个基序，这里我们证明了磷酸酪氨酸之前的保守疏水氨基酸对于与SHP-1结合并激活SHP-1是关键的，对应于杀伤细胞抑制受体序列的肽，大多数SH2结构域与磷酸肽的相互作用只需要磷酸化的Rosine和酪氨酸下游的三个残基。相反，能够结合或激活SHP-1的最短的肽还包括磷酸酪氨酸上游的两个残基，与SHP-1的两个SH2结构域相互作用的杀伤细胞抑制受体细胞质尾部对应的双磷酸肽是SHP-1最有效的激活剂，酪氨酸上游的疏水残基也是生物磷酸肽的关键，SHP-1结合基序中酪氨酸上游两个残基的疏水氨基酸的贡献可能是抑制性受体与提供激活信号的受体的重要区别。
SHP-1 is a protein-tyrosine phosphatase associated with inhibition of activation pathways in hematopoietic cells, The catalytic activity of SHP-1 is regulated by its two SH2 (Src homology 2) domains; phosphotyrosine peptides that bind to the SH2 domains activate SHP-1, The consensus sequence (I/V)XYXX(L/V) is present in the cytoplasmic tails of several lymphocyte receptors that interact with the second SH2 domain of SHP-1, In several of these receptors, there are two or three occurrences of the motif, Here we show that the conserved hydrophobic amino acid preceding the phosphotyrosine is critical for binding to and activation of SHP-1 by peptides corresponding to sequences from killer cell inhibitory receptors, The interaction of most SH2 domains with phosphopeptides requires only the phosphoty rosine and the three residues downstream of the tyrosine. In contrast, the shortest peptide able to bind or activate SHP-1 also included the two residues upstream of the phosphotyrosine, A biphosphopeptide corresponding to the cytoplasmic tail of a killer cell inhibitory receptor with the potential to interact simultaneously with both SH2 domains of SHP-1 was the most potent activator of SHP-1, The hydrophobic residue upstream of the tyrosine was also critical in the context of the biphosphopeptide, The contribution of a hydrophobic amino acid two residues upstream of the tyrosine in the SHP-1-binding motif may be an important feature that distinguishes inhibitory receptors from those that provide activation signals.