The self-inhibited structure of full-length PCSK9 at 1.9 Å reveals structural homology with resistin within the C-terminal domain

Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121

Edited by James A. Wells, University of California, San Francisco, CA, and approved July 25, 2007 (received for review April 12, 2007)

Abstract

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-Å 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.

Footnotes

*To whom correspondence should be addressed. E-mail: gspraggo{at}gnf.org
Author contributions: E.N.H., M.W.K., J.L., J.L.H., S.A.L., and G.S. designed research; E.N.H., M.W.K., and G.S. performed research; E.N.H., J.L., and G.S. analyzed data; and J.L., J.L.H., S.A.L., and G.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The structure reported in this paper has been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2QTW).
This article contains supporting information online at www.pnas.org/cgi/content/full/0703402104/DC1.
Abbreviations:

ADH,

autosomal dominant hypercholesterolemia;

CHD,

coronary heart disease;

LDL,

low-density lipoprotein;

NARC-1,

neural apoptosis-regulated convertase 1;

PCSK9,

prohormone convertase subtilisin kexin-9;

CRD,

cysteine-rich domain.