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首页> 外文期刊>Biochemistry >Substrate Specificity of Protein Tyrosine Phosphatases 1B, RPTPα, SHP-1, and SHP-2
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Substrate Specificity of Protein Tyrosine Phosphatases 1B, RPTPα, SHP-1, and SHP-2

机译：酪氨酸磷酸酶1B，RPTPα，SHP-1和SHP-2的底物特异性

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摘要

We determined the substrate specificities of the protein tyrosinenphosphatases (PTPs) PTP1B, RPTPR, SHP-1, and SHP-2 by on-beadnscreening of combinatorial peptide libraries and solution-phase kinetic analysisnof individually synthesized phosphotyrosyl (pY) peptides. These PTPs exhibitndifferent levels of sequence specificity and catalytic efficiency. The catalyticndomain of RPTPR has very weak sequence specificity and is approximately 2norders of magnitude less active than the other three PTPs. The PTP1Bncatalytic domain hasmodest preference for acidic residues on both sides of pY,nis highly active toward multiply phosphorylated peptides, but disfavors basicnresidues at any position, a Gly at the pY-1 position, or a Pro at the pYþ1nposition. By contrast, SHP-1 and SHP-2 share similar but much narrower substrate specificities, with a strong preference for acidicnand aromatic hydrophobic amino acids on both sides of the pY residue. An efficient SHP-1/2 substrate generally contains two ornmore acidic residues on the N-terminal side and one or more acidic residues on the C-terminal side of pY but no basic residues.nSubtle differences exist between SHP-1 and SHP-2 in that SHP-1 has a stronger preference for acidic residues at the pY-1 andnpYþ1 positions and the two SHPs prefer acidic residues at different positions N-terminal to pY. A survey of the known proteinnsubstrates of PTP1B, SHP-1, and SHP-2 shows an excellent agreement between the in vivo dephosphorylation pattern and the innvitro specificity profiles derived from library screening. These results suggest that different PTPs have distinct sequence specificitynprofiles and the intrinsic activity/specificity of the PTP domain is an important determinant of the enzyme’s in vivo substratenspecificity
机译：我们通过组合肽库的beadn筛选和单独合成的磷酸酪氨酸（pY）肽的溶液相动力学分析，确定了蛋白质酪氨酸磷酸酶（PTPs）PTP1B，RPTPR，SHP-1和SHP-2的底物特异性。这些PTP表现出不同的序列特异性和催化效率。 RPTPR的催化结构域具有非常弱的序列特异性，并且比其他三个PTP的活性低约2n个数量级。 PTP1Bn催化结构域对pY两侧的酸性残基有中等偏爱，对多重磷酸化肽具有高活性，但在任何位置都不利于碱性残基，在pY-1位置处是Gly，在pYþ1n位置处是Pro。相比之下，SHP-1和SHP-2具有相似但较窄的底物特异性，在pY残基的两侧均强烈偏爱酸性和芳族疏水氨基酸。有效的SHP-1 / 2底物通常在pY的N端侧包含两个或多个酸性残基，在pY的C端侧包含一个或多个酸性残基，但没有碱性残基.n SHP-1和SHP-2之间存在细微差异。因为SHP-1对pY-1和npYþ1位置的酸性残基有更强的偏爱，并且两个SHP对pY N端不同位置的酸性残基更喜欢。对PTP1B，SHP-1和SHP-2的已知蛋白底物进行的调查显示，体内脱磷酸化模式与衍生自文库筛选的体外特异性谱之间有着极好的一致性。这些结果表明，不同的PTP具有不同的序列特异性，而PTP结构域的内在活性/特异性是酶体内底物特异性的重要决定因素。

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