Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal dysplasia tarda
Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal dysplasia tarda
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DOI：
10.1074/jbc.m207436200
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发表时间：
2002-12-20
影响因子：
4.8
通讯作者：
Oh, BH
中科院分区：
文献类型：
--
作者：
Jang, SB;Kim, YG;Oh, BH
SEDL是真核生物进化过程中高度保守的蛋白质。SEDL基因的缺失或点突变是遗传病迟发性脊柱骨盆发育不良(SEDT)的原因，SEDT是一种X连锁骨骼疾病。SEDL被认为是运输蛋白颗粒(TRapp)的一个组成部分，在内质网到高尔基体小泡的运输中起着至关重要的作用。在这里，我们报告了SEDL的2.4埃分辨率结构，它揭示了与两个SNARE Ykt6p和Sec22b的N端调控结构域的结构出人意料的相似，尽管这些蛋白质没有序列同源性。SEDL的相似性和异常多的暴露于溶剂中的非极性残基的存在表明，它通过多种蛋白质-蛋白质相互作用发挥调节和/或适配功能。在导致SEDT的四个已知错义突变中，三个突变(S73L、F83S、V130D)映射到蛋白质内部，在那里突变会破坏结构，第四个(D47Y)位于突变可能破坏与配对蛋白质的功能相互作用的表面。
SEDL is an evolutionarily highly conserved protein in eukaryotic organisms. Deletions or point mutations in the SEDL gene are responsible for the genetic disease spondyloepiphyseal dysplasia tarda (SEDT), an X-linked skeletal disorder. SEDL has been identified as a component of the transport protein particle (TRAPP), critically involved in endoplasmic reticulum-to-Golgi vesicle transport. Herein, we report the 2.4 Angstrom resolution structure of SEDL, which reveals an unexpected similarity to the structures of the N-terminal regulatory domain of two SNAREs, Ykt6p and Sec22b, despite no sequence homology to these proteins. The similarity and the presence of unusually many solvent-exposed apolar residues of SEDL suggest that it serves regulatory and/or adaptor functions through multiple protein-protein interactions. Of the four known missense mutations responsible for SEDT, three mutations (S73L, F83S, V130D) map to the protein interior, where the mutations would disrupt the structure, and the fourth (D47Y) on a surface at which the mutation may abrogate functional interactions with a partner protein.