Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Aapistie 7, 90220 Oulu, Finland.
Biomolecules. 2020 Apr 24;10(4):660. doi: 10.3390/biom10040660.
The functions of the annexin family of proteins involve binding to Ca, lipid membranes, other proteins, and RNA, and the annexins share a common folded core structure at the C terminus. Annexin A11 (AnxA11) has a long N-terminal region, which is predicted to be disordered, binds RNA, and forms membraneless organelles involved in neuronal transport. Mutations in AnxA11 have been linked to amyotrophic lateral sclerosis (ALS). We studied the structure and stability of AnxA11 and identified a short stabilising segment in the N-terminal end of the folded core, which links domains I and IV. The crystal structure of the AnxA11 core highlights main-chain hydrogen bonding interactions formed through this bridging segment, which are likely conserved in most annexins. The structure was also used to study the currently known ALS mutations in AnxA11. Three of these mutations correspond to buried Arg residues highly conserved in the annexin family, indicating central roles in annexin folding. The structural data provide starting points for detailed structure-function studies of both full-length AnxA11 and the disease variants being identified in ALS.
annexin 蛋白家族的功能包括与 Ca、脂质膜、其他蛋白和 RNA 结合，并且 annexin 在 C 末端共享一个共同的折叠核心结构。Annexin A11 (AnxA11) 具有长的 N 端区域，预测为无序，与 RNA 结合，并形成无膜细胞器，参与神经元运输。AnxA11 中的突变与肌萎缩侧索硬化症 (ALS) 有关。我们研究了 AnxA11 的结构和稳定性，并在折叠核心的 N 端末端确定了一个短的稳定化片段，该片段连接结构域 I 和 IV。AnxA11 核心的晶体结构突出了通过该桥接片段形成的主链氢键相互作用，这些相互作用可能在大多数 annexin 中保守。该结构还用于研究目前已知的 AnxA11 中的 ALS 突变。其中三个突变对应于 annexin 家族中高度保守的埋藏 Arg 残基，表明在 annexin 折叠中起核心作用。结构数据为全长 AnxA11 和在 ALS 中鉴定出的疾病变体的详细结构功能研究提供了起点。
