Department of Pharmacology, School of Medicine, Case Western Reserve University, OH, USA.
J Struct Biol. 2012 Dec;180(3):439-46. doi: 10.1016/j.jsb.2012.07.011. Epub 2012 Aug 7.
Autosomal dominant late-onset retinal macular degeneration (L-ORMD) is caused by a single S163R mutation in the C1q and tumor necrosis factor-related protein 5 (C1QTNF5) gene. The C1QTNF5 gene encodes a secreted and membrane-associated protein involved in adhesion of retinal pigmented epithelial cells (RPE) to Bruch's membrane. The crystal structure of the trimeric globular domain of human C1QTNF5 at 1.34Å resolution reveals unique features of this novel C1q family member. It lacks a Ca²⁺-binding site, displays a remarkable non-uniform distribution of surface electrostatic potentials and possesses a unique sequence (F₁₈₁F₁₈₂G₁₈₃G₁₈₄W₁₈₅P₁₈₆) that forms a hydrophobic plateau surrounded by Lys and Arg residues with a solvent cavity underneath. S₁₆₃ forms a hydrogen bond with F₁₈₂ in a hydrophobic area extending to the hydrophobic plateau. The pathogenic mutation S163R disrupts this hydrogen bonding and positively charges these hydrophobic areas. Thus, our analysis provides insights into the structural basis of the L-ORMD disease mechanism.
常染色体显性晚发性视网膜黄斑变性（L-ORMD）是由 C1q 和肿瘤坏死因子相关蛋白 5（C1QTNF5）基因中的单个 S163R 突变引起的。C1QTNF5 基因编码一种分泌型和膜相关蛋白，参与视网膜色素上皮细胞（RPE）与布鲁赫膜的黏附。人 C1QTNF5 三聚体球形结构域的 1.34Å 分辨率晶体结构揭示了这种新型 C1q 家族成员的独特特征。它缺乏一个 Ca²⁺结合位点，显示出表面静电势的显著非均匀分布，并具有独特的序列（F₁₈₁F₁₈₂G₁₈₃G₁₈₄W₁₈₅P₁₈₆），形成一个疏水平台，周围是赖氨酸和精氨酸残基，下面有一个溶剂腔。S₁₆₃与 F₁₈₂形成氢键，氢键延伸到疏水平台。致病性突变 S163R 破坏了这种氢键，并使这些疏水区域带正电荷。因此，我们的分析为 L-ORMD 疾病机制的结构基础提供了深入了解。
