Department of Agricultural Biotechnology, Centre for Food Safety and Toxicology, Centre for Food and Bioconvergence, Research Institute for Agriculture and Life Sciences, CALS, Seoul National University, Seoul, 08826, Republic of Korea.
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan, 46241, Republic of Korea.
Biochem Biophys Res Commun. 2021 Apr 23;550:191-196. doi: 10.1016/j.bbrc.2021.02.102. Epub 2021 Mar 9.
Lamins are nuclear intermediate filament proteins that play an essential role in maintaining the nuclear structure by forming a 3-D meshwork. Lamins consist of the N-terminal unstructured head, the coiled-coil rod domain, and the C-terminal tail, which is mostly unstructured except for the Ig-like domain. To date, the Ig-like domain has been characterized as a monomeric structure. Here, we determined the crystal structures of human lamin A/C, including the Ig-like domain and its N- and C-terminal flanking sequences. Interestingly, the structures showed a homodimer formed by beta-strand interactions between the N- and C-terminal flanking sequences. This interaction also provides a molecular implication for the creation of a 3-D meshwork between the 3.5-nm-thick filaments. Furthermore, we determined the crystal structure of the corresponding region of lamin B1. The structure showed a similar dimeric assembly, also formed by beta-strand interactions, albeit the intersubunit distance was much shorter. Since the Ig-like domain contains many genetic hotspots causing lamin-related diseases in lamin A/C, our findings will help understand the detailed assembly of lamins in a 3-D meshwork structure and lamin-related diseases at the molecular level.
核纤层蛋白是核内中间丝蛋白，通过形成三维网格结构对维持核结构起着至关重要的作用。核纤层蛋白由 N 端无规卷曲头部、螺旋卷曲杆域和 C 端尾部组成，除免疫球蛋白样结构域外，C 端尾部大多无规则卷曲。迄今为止，免疫球蛋白样结构域已被鉴定为单体结构。在这里，我们确定了包括免疫球蛋白样结构域及其 N 端和 C 端侧翼序列在内的人核纤层蛋白 A/C 的晶体结构。有趣的是，结构显示由 N 端和 C 端侧翼序列之间的β-链相互作用形成同源二聚体。这种相互作用也为 3.5nm 厚的细丝之间形成三维网格结构提供了分子解释。此外，我们还确定了核纤层蛋白 B1 的相应区域的晶体结构。该结构显示出类似的二聚体组装，同样由β-链相互作用形成，尽管亚基间距离要短得多。由于免疫球蛋白样结构域包含许多导致核纤层蛋白 A/C 中与核纤层蛋白相关疾病的遗传热点，我们的发现将有助于在分子水平上理解核纤层蛋白在三维网格结构中的详细组装和与核纤层蛋白相关的疾病。
