Hampton Eric N, Knuth Mark W, Li Jun, Harris Jennifer L, Lesley Scott A, Spraggon Glen
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14604-9. doi: 10.1073/pnas.0703402104. Epub 2007 Sep 5.
Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) are strongly associated with levels of low-density lipoprotein cholesterol in the blood plasma and, thereby, occurrence or resistance to atherosclerosis and coronary heart disease. Despite this importance, relatively little is known about the biology of PCSK9. Here, the crystal structure of a full-length construct of PCSK9 solved to 1.9-A resolution is presented. The structure contains a fully folded C-terminal cysteine-rich domain (CRD), showing a distinct structural similarity to the resistin homotrimer, a small cytokine associated with obesity and diabetes. This structural relationship between the CRD of PCSK9 and the resistin family is not observed in primary sequence comparisons and strongly suggests a distant evolutionary link between the two molecules. This three-dimensional homology provides insight into the function of PCSK9 at the molecular level and will help to dissect the link between PCSK9 and CHD.
前蛋白转化酶枯草溶菌素/九型（PCSK9）中的突变与血浆中低密度脂蛋白胆固醇水平密切相关，进而与动脉粥样硬化和冠心病的发生或抗性相关。尽管具有这种重要性，但人们对PCSK9的生物学特性了解相对较少。在此，展示了分辨率为1.9埃的PCSK9全长构建体的晶体结构。该结构包含一个完全折叠的富含半胱氨酸的C末端结构域（CRD），与抵抗素同三聚体具有明显的结构相似性，抵抗素是一种与肥胖和糖尿病相关的小细胞因子。在一级序列比较中未观察到PCSK9的CRD与抵抗素家族之间的这种结构关系，这强烈表明这两种分子之间存在遥远的进化联系。这种三维同源性为从分子水平深入了解PCSK9的功能提供了线索，并将有助于剖析PCSK9与冠心病之间的联系。
