Department of Agricultural Biotechnology, Center for Food and Bioconvergence, and Research Institute of 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. 2022 Dec 31;637:210-217. doi: 10.1016/j.bbrc.2022.10.070. Epub 2022 Oct 26.
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder caused by C-terminally truncated lamin A, termed as the pre-progerin product. Progerin is a C-terminally farnesylated protein derived from pre-progerin, which causes nuclear deformation at the inner-nuclear membrane. As an alternative or additional mechanism, a farnesylation-independent abnormal interaction between the C-terminus of progerin and Ig-like domain has been proposed. However, the molecular mechanism underlying the role of unfarnesylated C-terminus of pre-progerin in HGPS remains largely unknown. In this study, we determined the crystal structures of C-terminal peptide of progerin and Ig-like domain of lamin A/C. Results showed that the C-terminal cysteine residue of progerin forms a disulfide bond with the only cysteine residue of the Ig-like domain. This finding suggested that unfarnesylated progerin can form a disulfide bond with the Ig-like domain in the lamin meshwork. The Alphafold2-assisted docking structure showed that disulfide bond formation was promoted by a weak interaction between the groove of Ig-like domain and the unfarnesylated C-terminal tail region of progerin. Our results provide molecular insights into the normal aging process as well as premature aging of humans.
亨廷顿氏舞蹈症 - 早老综合征（HGPS）是一种由端截断的核纤层蛋白 A 引起的过早衰老疾病，称为前核纤层蛋白产物。前核纤层蛋白是一种端巴豆酰化蛋白，来源于前核纤层蛋白，导致核内膜内层的核变形。作为一种替代或附加机制，已经提出了前核纤层蛋白的 C 末端与 Ig 样结构域之间的非巴豆酰化异常相互作用。然而，HGPS 中未巴豆酰化的前核纤层蛋白 C 末端在其中的作用的分子机制在很大程度上仍然未知。在这项研究中，我们确定了前核纤层蛋白 C 末端肽和核纤层蛋白 A/C 的 Ig 样结构域的晶体结构。结果表明，前核纤层蛋白的 C 末端半胱氨酸残基与 Ig 样结构域的唯一半胱氨酸残基形成二硫键。这一发现表明，未巴豆酰化的前核纤层蛋白可以与核纤层蛋白网络中的 Ig 样结构域形成二硫键。Alphafold2 辅助对接结构表明，二硫键的形成是由 Ig 样结构域的凹槽与前核纤层蛋白的未巴豆酰化 C 末端尾部区域之间的弱相互作用促进的。我们的结果为正常衰老过程以及人类的过早衰老提供了分子见解。
