STRUCTURE OF AN SH2 DOMAIN OF THE P85-ALPHA SUBUNIT OF PHOSPHATIDYLINOSITOL-3-OH KINASE
STRUCTURE OF AN SH2 DOMAIN OF THE P85-ALPHA SUBUNIT OF PHOSPHATIDYLINOSITOL-3-OH KINASE
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DOI：
10.1038/358684a0
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发表时间：
1992-08-20
期刊：
影响因子：
64.8
通讯作者：
CAMPBELL, ID
中科院分区：
文献类型：
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作者：
BOOKER, GW;BREEZE, AL;CAMPBELL, ID
受体蛋白酪氨酸激酶通过特定酪氨酸残基的磷酸化，产生高亲和力结合位点，指导多酶信号复合物的组装1,2。许多这些信号蛋白，包括磷脂酶 C-gamma、GTP 酶激活蛋白和磷脂酰肌醇-3-OH 激酶，都含有 src 同源 2 (SH2) 结构域，该结构域以高亲和力和特异性与酪氨酸磷酸化序列结合 3,4。最近的研究强调了 SH2 结构域在信号传导中发挥的关键作用，这些研究表明血小板源性生长因子受体上特定磷酸化位点的突变会损害其与磷脂酰肌醇-3-OH 激酶的关联，从而阻止生长因子诱导的有丝分裂5,6。在这里，我们报告了使用多维核磁共振波谱测定的磷脂酰肌醇-3-OH激酶85K调节亚基中分离的SH2结构域的溶液结构。该结构的特点是 β-折叠的中心区域两侧是两个 α-螺旋，具有高度灵活的环，靠近先前通过定点诱变鉴定的功能重要残基7,8。
RECEPTOR protein-tyrosine kinases, through phosphorylation of specific tyrosine residues, generate high-affinity binding sites which direct assembly of multienzyme signalling complexes1,2. Many of these signalling proteins, including phospholipase C-gamma, GTPase-activating protein and phosphatidylinositol-3-OH kinase, contain src-homology 2 (SH2) domains, which bind with high affinity and specificity to tyrosine-phosphorylated sequences3,4. The critical role played by SH2 domains in signalling has been highlighted by recent studies showing that mutation of specific phosphorylation sites on the platelet-derived growth factor receptor impair its association with phosphatidylinositol-3-OH kinase, preventing growth factor-induced mitogenesis5,6. Here we report the solution structure of an isolated SH2 domain from the 85K regulatory subunit of phosphatidylinositol-3-OH kinase, determined using multidimensional nuclear magnetic resonance spectroscopy. The structure is characterized by a central region of beta-sheet flanked by two alpha-helices, with a highly flexible loop close to functionally important residues previously identified by site-directed mutagenesis7,8.