The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein
The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein
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DOI：
10.1128/mcb.16.11.6229
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发表时间：
1996-11
影响因子：
5.3
通讯作者：
J. Borg;J. Ooi;E. Levy;B. Margolis
中科院分区：
文献类型：
--
作者：
J. Borg;J. Ooi;E. Levy;B. Margolis
Shc和IRS-1的磷酸酪氨酸相互作用（PI）结构域（也称为PTB或磷酸酪氨酸结合结构域）是最近描述的结合酪氨酸残基上磷酸化的肽的结构域。PI/PTB结构域与Src同源2（SH 2）结构域的不同之处在于它们的结合特异性由位于磷酸酪氨酸的氨基末端而不是羧基末端的残基决定。最近，已经认识到其他细胞质蛋白也含有PI结构域。我们现在表明，X11的PI结构域和FE 65的PI结构域之一，两种神经元蛋白，结合到淀粉样前体蛋白（β）APP的胞质结构域。（β）APP是一种完整的跨膜糖蛋白，其细胞功能尚不清楚。APP的加工途径之一导致A（beta）的分泌，A（beta）是阿尔茨海默病患者脑实质和血管壁中沉积的淀粉样蛋白的主要成分。我们已经发现，X11 PI结构域结合（β）APP胞内结构域中的YENPTY基序，其与结合Shc和IRS-1 PI/PTB结构域的NPXY基序惊人地相似。然而，与Shc PI/PTB结构域结合的情况不同，YENPTY基序的酪氨酸磷酸化对于（β）APP与X11或FE 65的结合不是必需的。FE 65 PI结构域的结合位点似乎与X11的结合位点不同，因为YENPTY基序内的突变差异性地影响X11和FE 65的结合。使用定点突变，我们已经确定了一个关键的残基内的PI结构域参与X11和FE 65结合（β）APP。X11或FE 65 PI结构域的YENPTY基序（β）APP的残基的结合，确定PI结构域作为一般的蛋白质相互作用域，并可能有重要的影响（β）APP的加工。
The phosphotyrosine interaction (PI) domains (also known as the PTB, or phosphotyrosine binding, domains) of Shc and IRS-1 are recently described domains that bind peptides phosphorylated on tyrosine residues. The PI/PTB domains differ from Src homology 2 (SH2) domains in that their binding specificity is determined by residues that lie amino terminal and not carboxy terminal to the phosphotyrosine. Recently, it has been appreciated that other cytoplasmic proteins also contain PI domains. We now show that the PI domain of X11 and one of the PI domains of FE65, two neuronal proteins, bind to the cytoplasmic domain of the amyloid precursor protein ((beta)APP). (beta)APP is an integral transmembrane glycoprotein whose cellular function is unknown. One of the processing pathways of (beta)APP leads to the secretion of A(beta), the major constituent of the amyloid deposited in the brain parenchyma and vessel walls of Alzheimer's disease patients. We have found that the X11 PI domain binds a YENPTY motif in the intracellular domain of (beta)APP that is strikingly similar to the NPXY motifs that bind the Shc and IRS-1 PI/PTB domains. However, unlike the case for binding of the Shc PI/PTB domain, tyrosine phosphorylation of the YENPTY motif is not required for the binding of (beta)APP to X11 or FE65. The binding site of the FE65 PI domain appears to be different from that of X11, as mutations within the YENPTY motif differentially affect the binding of X11 and FE65. Using site-directed mutagenesis, we have identified a crucial residue within the PI domain involved in X11 and FE65 binding to (beta)APP. The binding of X11 or FE65 PI domains to residues of the YENPTY motif of (beta)APP identifies PI domains as general protein interaction domains and may have important implications for the processing of (beta)APP.