Department of Dermatology, Yale University, New Haven, CT, 06520, USA.
Department of Dermatology, Yale University, New Haven, CT, 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA.
Curr Opin Cell Biol. 2021 Feb;68:132-143. doi: 10.1016/j.ceb.2020.10.001. Epub 2020 Nov 12.
Intermediate filaments (IFs) are key players in multiple cellular processes throughout human tissues. Their biochemical and structural properties are important for understanding filament assembly mechanisms, for interactions between IFs and binding partners, and for developing pharmacological agents that target IFs. IF proteins share a conserved coiled-coil central-rod domain flanked by variable N-terminal 'head' and C-terminal 'tail' domains. There have been several recent advances in our understanding of IF structure from the study of keratins, glial fibrillary acidic protein, and lamin. These include discoveries of (i) a knob-pocket tetramer assembly mechanism in coil 1B; (ii) a lamin-specific coil 1B insert providing a one-half superhelix turn; (iii) helical, yet flexible, linkers within the rod domain; and (iv) the identification of coil 2B residues required for mature filament assembly. Furthermore, the head and tail domains of some IFs contain low-complexity aromatic-rich kinked segments, and structures of IFs with binding partners show electrostatic surfaces are a major contributor to complex formation. These new data advance the connection between IF structure, pathologic mutations, and clinical diseases in humans.
中间丝（IFs）是人类组织中多种细胞过程的关键参与者。它们的生化和结构特性对于理解纤维组装机制、IFs 与结合伴侣之间的相互作用以及开发靶向 IFs 的药理学制剂都很重要。IF 蛋白共享一个保守的卷曲螺旋中央-杆域，两侧是可变的 N 端“头部”和 C 端“尾部”域。最近在研究角蛋白、神经胶质纤维酸性蛋白和核纤层蛋白时，我们对 IF 结构有了一些新的认识。这些发现包括：（i）在 coil 1B 中发现了一个旋钮口袋四聚体组装机制；（ii）一个独特的 lamin-specific coil 1B 插入提供了半圈超螺旋；（iii）在杆域内存在螺旋但灵活的连接子；（iv）鉴定出成熟纤维组装所需的 coil 2B 残基。此外，一些 IF 的头部和尾部域包含低复杂度富含芳香族的扭曲片段，并且与结合伴侣的 IF 结构表明静电表面是形成复合物的主要贡献者。这些新数据促进了 IF 结构、病理突变和人类临床疾病之间的联系。
