A Structural Model for the Core Nup358-BicD2 Interface.
A Structural Model for the Core Nup358-BicD2 Interface.
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DOI：
10.3390/biom13101445
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发表时间：
2023-09-26
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
动力蛋白马达促进微管上大多数负端定向运输事件。动力蛋白接头 Bicaudal D2 (BicD2) 将动力蛋白机制招募到多种细胞货物中进行运输，包括 Nup358，它促进核定位途径，这对于不同脑祖细胞的分化至关重要。此前，我们证明Nup358在与BicD2结合后形成“货物识别α螺旋”；然而，BicD2-Nup358 接口的具体细节仍不清楚。在这里，我们使用 AlphaFold2，并辅以两个额外的对接程序（HADDOCK 和 ClusPro）以及诱变，以表明 Nup358 货物识别 α-螺旋以反平行方式与残基 747 和 774 之间的 BicD2 结合，形成螺旋束。我们确定了两个对于稳定界面很重要的分子间盐桥。此外，我们发现了由 Nup358 的本质无序区域介导的二级界面，该区域直接位于货物识别 α 螺旋的 N 端，并与残基 774 和 800 之间的 BicD2 结合。这与结合竞争性货物接头 Rab6 的 BicD2 结构域相同，这对于高尔基体衍生的分泌囊泡的运输很重要。我们的结果为动力蛋白适配器 BicD2 的货物识别和选择奠定了结构基础，这促进了对大脑发育很重要的运输途径。
Dynein motors facilitate the majority of minus-end-directed transport events on microtubules. The dynein adaptor Bicaudal D2 (BicD2) recruits the dynein machinery to several cellular cargo for transport, including Nup358, which facilitates a nuclear positioning pathway that is essential for the differentiation of distinct brain progenitor cells. Previously, we showed that Nup358 forms a “cargo recognition α-helix” upon binding to BicD2; however, the specifics of the BicD2-Nup358 interface are still not well understood. Here, we used AlphaFold2, complemented by two additional docking programs (HADDOCK and ClusPro) as well as mutagenesis, to show that the Nup358 cargo-recognition α-helix binds to BicD2 between residues 747 and 774 in an anti-parallel manner, forming a helical bundle. We identified two intermolecular salt bridges that are important to stabilize the interface. In addition, we uncovered a secondary interface mediated by an intrinsically disordered region of Nup358 that is directly N-terminal to the cargo-recognition α-helix and binds to BicD2 between residues 774 and 800. This is the same BicD2 domain that binds to the competing cargo adapter Rab6, which is important for the transport of Golgi-derived and secretory vesicles. Our results establish a structural basis for cargo recognition and selection by the dynein adapter BicD2, which facilitates transport pathways that are important for brain development.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
5
作者：
Honorato RV;Koukos PI;Jiménez-García B;Tsaregorodtsev A;Verlato M;Giachetti A;Rosato A;Bonvin AMJJ
通讯作者：
Bonvin AMJJ
影响因子：
64.8
作者：
Chaaban S;Carter AP
通讯作者：
Carter AP
影响因子：
7.8
作者：
MAUL, GG;MAUL, HM;LIEBERMAN, MW
通讯作者：
LIEBERMAN, MW
影响因子：
14.8
作者：
Kozakov D;Hall DR;Xia B;Porter KA;Padhorny D;Yueh C;Beglov D;Vajda S
通讯作者：
Vajda S