A phenylalanine zipper mediates APS dimerization
A phenylalanine zipper mediates APS dimerization
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DOI：
10.1038/nsmb829
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发表时间：
2004-10-01
影响因子：
16.8
通讯作者：
Shoelson, SE
中科院分区：
文献类型：
--
作者：
Dhe-Sirano, D;Werner, ED;Shoelson, SE
APS、SH2-B和LNK蛋白是激活和调节受体酪氨酸激酶和JAK/STAT信号的接头。我们现在证明了保守的N-末端结构域介导了APS的同源二聚化。我们用溴离子相位法测定了二聚化区的晶体结构，其分辨率为1.7埃。每个分子为紧凑的四股螺旋束贡献两个螺旋，该束具有平分-U拓扑结构。它最明显的特征是在结构域核心有一堆交错的苯丙氨酸侧链。这些残基产生了一个新的基序，我们称之为“苯丙氨酸拉链”，它对二聚反应至关重要。一种新开发的桥接酵母三杂交实验表明，APS通过其SH2和二聚化结构域二聚化JAK2、胰岛素受体和IGF1受体激酶。通过苯丙氨酸拉链结构域的二聚化为激活和调节酪氨酸激酶活性提供了一种机制，即使在没有细胞外配体的情况下也是如此。
The APS, SH2-B and LNK proteins are adapters that activate and modulate receptor tyrosine kinase and JAK/STAT signaling. We now show that a conserved N-terminal domain mediates APS homodimerization. We determined the crystal structure of the dimerization domain at a resolution of 1.7 Angstrom using bromide ion MAD phasing. Each molecule contributes two helices to a compact four-helix bundle having a bisecting-U topology. Its most conspicuous feature is a stack of interdigitated phenylalanine side chains at the domain core. These residues create a new motif we refer to as a 'phenylalanine zipper', which is critical to dimerization. A newly developed bridging yeast tri-hybrid assay showed that APS dimerizes JAK2, insulin receptor and IGF1 receptor kinases using its SH2 and dimerization domains. Dimerization via the phenylalanine zipper domain provides a mechanism for activating and modulating tyrosine kinase activity even in the absence of extracellular ligands.