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

Academic Article
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Overview

authors

  • Hampton, E. N.
  • Knuth, M. W.
  • Li, J.
  • Harris, J. L.
  • Lesley, Scott
  • Spraggon, G.

publication date

  • September 2007

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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-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.

subject areas

  • Amino Acid Sequence
  • Baculoviridae
  • Binding Sites
  • Catalytic Domain
  • Crystallography, X-Ray
  • Cysteine
  • Disulfides
  • Furin
  • Histidine
  • Models, Chemical
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Oligopeptides
  • Proprotein Convertases
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Resistin
  • Saccharomyces cerevisiae Proteins
  • Sequence Homology, Amino Acid
  • Serine Endopeptidases
  • Static Electricity
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Research

keywords

  • adipocytokine
  • hypercholesterolemia
  • low-density lipoprotein receptor
  • proprotein convertase
  • x-ray crystallography
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Identity

PubMed Central ID

  • PMC1976225

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0703402104

PubMed ID

  • 17804797
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Additional Document Info

start page

  • 14604

end page

  • 14609

volume

  • 104

issue

  • 37

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