The regulatory domains of the lipid exporter ABCA1 form domain swapped latches.
The regulatory domains of the lipid exporter ABCA1 form domain swapped latches.
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DOI：
10.1371/journal.pone.0262746
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发表时间：
2022
期刊：
影响因子：
3.7
通讯作者：
Segrest JP
中科院分区：
文献类型：
--
作者：
Aller SG;Segrest JP
ABCA 1和ABCA 4是神秘的，因为它们以相反的方向运输底物，但共享>50%的氨基酸同一性。ABCA 4输入脂质缀合物，但ABCA 1输出脂质。两者都水解ATP以驱动运输，并且都在一级结构中包含核苷酸结合结构域（NBD）之后的细胞质调节结构域（RD）。包括ABCA 4在内的几个ABC导入器的三级结构表明，每个RD形成了一个域交换锁存器，该锁存器锁定在相对的RD上，并将NBD保持在一起。至关重要的是，编码RD及其桥的序列在整个ABC-A亚家族中是最保守的。在ABCA 1的原始cryo-EM结构中，在没有交叉的情况下对RD进行建模。在仔细检查了冷冻EM密度图和ABCA 4的最新结构之后，我们提出ABCA 1的RD也形成了域交换锁存器。一个完善的ABCA 1模型含有锁存器表现出显着改善整体蛋白质的几何形状。重要的是，保守的交叉序列导致RD结构域交换是直接支持的原始cryo-EM密度图的ABCA 1，似乎已被忽视。我们改进的ABCA 1模型表明，ABCA 1，尽管是一个出口商，具有高度约束的NBD的可能性，这表明一种运输机制，是不同于“交替访问”。
ABCA1 and ABCA4 are enigmatic because they transport substrates in opposite directions yet share >50% amino acid identity. ABCA4 imports lipid conjugates but ABCA1 exports lipids. Both hydrolyze ATP to drive transport, and both contain cytoplasmic regulatory domains (RDs) following nucleotide-binding domains (NBDs) in the primary structure. The tertiary structures of several ABC importers, including ABCA4, show that each RD forms a domain-swapped latch that locks onto the opposing RD and holds the NBDs close together. Crucially, sequences encoding the RDs and their bridges are among the most conserved in the entire ABC-A subfamily. In the original cryo-EM structure of ABCA1, the RDs were modeled without crossover. After close inspection of that cryo-EM density map and the recent structure of ABCA4, we propose that the RDs of ABCA1 also form a domain-swapped latch. A refined ABCA1 model containing latches exhibited significantly improved overall protein geometry. Critically, the conserved crossover sequence leading to the RD-domain swap is directly supported by the original cryo-EM density map of ABCA1 and appears to have been overlooked. Our refined ABCA1 model suggests the possibility that ABCA1, despite being an exporter, has highly restrained NBDs that suggest a transport mechanism that is distinct from ‘alternating access’.
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影响因子：
14.9
作者：
NCBI Resource Coordinators
通讯作者：
NCBI Resource Coordinators
影响因子：
16.6
作者：
Naoe, Youichi;Nakamura, Nozomi;Doi, Akihiro;Sawabe, Mia;Nakamura, Hiro;Shiro, Yoshitsugu;Sugimoto, Hiroshi
通讯作者：
Sugimoto, Hiroshi
影响因子：
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通讯作者：
Hassabis D
影响因子：
64.8
作者：
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通讯作者：
Chen, Jue
影响因子：
64.8
作者：
Hollenstein, Kaspar;Frei, Dominik C.;Locher, Kaspar P.
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