A ubiquitin-like domain is required for stabilizing the N-terminal ATPase module of human SMCHD1.
A ubiquitin-like domain is required for stabilizing the N-terminal ATPase module of human SMCHD1.
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稳定人 SMCHD1 的 N 端 ATP 酶模块需要类泛素结构域。
DOI：
10.1038/s42003-019-0499-y
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发表时间：
2019
影响因子：
5.9
通讯作者：
Shaw,NatalieD
中科院分区：
文献类型：
--
作者：
Pedersen,LarsC;Inoue,Kaoru;Kim,Susan;Perera,Lalith;Shaw,NatalieD
SMCHD 1基因的变体编码一种表观遗传阻遏物，它与先天性无鼻症和一种称为面肩肱型肌营养不良2型（FSHD 2）的迟发性肌营养不良症有关。这表明SMCHD 1在发育的时间和空间上具有多样性功能。SMCHD 1的C-末端包含一个SMC铰链结构域，其介导同源二聚化和染色质缔合，而N-末端区域的分子结构（其包含GHKL-ATP酶结构域）尚未得到很好的理解。我们目前的晶体结构的人SMCHD 1 N-末端ATP酶模块绑定到ATP作为一个功能性二聚体。二聚体是稳定的一个新的N-末端泛素样折叠和下游的换能器域。虽然疾病变体映射到似乎是关键的结构域间/分子间界面，但只有我们测试的FSHD 2特异性突变体构建体始终消除ATP酶活性和/或二聚化。这些数据表明，SMCHD 1的完整功能概况尚未确定。
Variants in the geneSMCHD1, which encodes an epigenetic repressor, have been linked to both congenital arhinia and a late-onset form of muscular dystrophy called facioscapulohumeral muscular dystrophy type 2 (FSHD2). This suggests that SMCHD1 has a diversity of functions in both developmental time and space. The C-terminal end of SMCHD1 contains an SMC-hinge domain which mediates homodimerization and chromatin association, whereas the molecular architecture of the N-terminal region, which harbors the GHKL-ATPase domain, is not well understood. We present the crystal structure of the human SMCHD1 N-terminal ATPase module bound to ATP as a functional dimer. The dimer is stabilized by a novel N-terminal ubiquitin-like fold and by a downstream transducer domain. While disease variants map to what appear to be critical interdomain/intermolecular interfaces, only the FSHD2-specific mutant constructs we tested consistently abolish ATPase activity and/or dimerization. These data suggest that the full functional profile of SMCHD1 has yet to be determined.