Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility
Meiotic chromosome synapsis depends on multivalent SYCE1-SIX6OS1 interactions that are disrupted in cases of human infertility
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DOI：
10.1126/sciadv.abb1660
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发表时间：
2020-09-01
期刊：
影响因子：
13.6
通讯作者：
Davies, Owen R.
中科院分区：
文献类型：
--
作者：
Sanchez-Saez, Fernando;Gomez-H, Laura;Davies, Owen R.
减数分裂的减数分裂依赖于联会复合体(SC)，联会复合体是一种超分子蛋白质集合，介导同源染色体的突触并促进交叉形成。哺乳动物SC有8个结构成分，包括SYCE1，这是已知在人类不孕不育中存在致病突变的唯一中央元件蛋白。我们结合小鼠遗传学、细胞和生化研究揭示了SYCE1与SC成分SIX6OS1经历了多价相互作用。SIX6OS1的N端与SYCE1‘S核心二聚体结构结合并破坏形成1：1的复合体，而其下游序列提供了明显的第二界面。这些接口分别被分别与非梗阻性无精子症和卵巢早衰(POF)相关的SYCE1突变破坏。携带SYCE1‘S POF突变和SIX6OS1’S N端靶向缺失的小鼠不育，并伴有染色体突触失败。我们的结论是，SYCE1-SIX6OS1两个结合界面都是SC组装所必需的，从而解释了SYCE1的S报道的临床突变导致人类不孕的原因。
Meiotic reductional division depends on the synaptonemal complex (SC), a supramolecular protein assembly that mediates homologous chromosomes synapsis and promotes crossover formation. The mammalian SC has eight structural components, including SYCE1, the only central element protein with known causative mutations in human infertility. We combine mouse genetics, cellular, and biochemical studies to reveal that SYCE1 undergoes multivalent interactions with SC component SIX6OS1. The N terminus of SIX6OS1 binds and disrupts SYCE1's core dimeric structure to form a 1:1 complex, while their downstream sequences provide a distinct second interface. These interfaces are separately disrupted by SYCE1 mutations associated with nonobstructive azoospermia and premature ovarian failure (POF), respectively. Mice harboring SYCE1's POF mutation and a targeted deletion within SIX6OS1's N terminus are infertile with failure of chromosome synapsis. We conclude that both SYCE1-SIX6OS1 binding interfaces are essential for SC assembly, thus explaining how SYCE1's reported clinical mutations give rise to human infertility.