self-inhibited structure of full-length PCSK9 at 1.9 Å reveals structural homology with resistin within the C-terminal domain
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...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 37; pp. 14604 - 14609 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
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United States
National Academy of Sciences
11.09.2007
National Acad Sciences |
Subjects | |
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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. |
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AbstractList | 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. 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. hypercholesterolemia low-density lipoprotein receptor proprotein convertase x-ray crystallography adipocytokine 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. 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. [PUBLICATION ABSTRACT] |
Author | Knuth, Mark W Li, Jun Spraggon, Glen Hampton, Eric N Harris, Jennifer L Lesley, Scott A |
Author_xml | – sequence: 1 fullname: Hampton, Eric N – sequence: 2 fullname: Knuth, Mark W – sequence: 3 fullname: Li, Jun – sequence: 4 fullname: Harris, Jennifer L – sequence: 5 fullname: Lesley, Scott A – sequence: 6 fullname: Spraggon, Glen |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17804797$$D View this record in MEDLINE/PubMed |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by James A. Wells, University of California, San Francisco, CA, and approved July 25, 2007 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. |
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Snippet | Mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) are strongly associated with levels of low-density lipoprotein cholesterol in the blood... |
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SubjectTerms | Active sites Amino Acid Sequence Amino acids Baculoviridae - genetics Binding Sites Biological Sciences Blood Blood plasma Cardiovascular disease Catalytic Domain Cells Crystal structure Crystallography, X-Ray Cysteine - chemistry Cytokines Disulfides Disulfides - chemistry Furin - chemistry Genetic mutation Histidine - chemistry Hypercholesterolemia Models, Chemical Models, Molecular Molecular Sequence Data Molecules Mutation Oligopeptides - chemistry Proprotein Convertase 9 Proprotein Convertases - chemistry Protein Conformation Protein Structure, Secondary Protein Structure, Tertiary Proteins Receptors Resistin - chemistry Saccharomyces cerevisiae Proteins - chemistry Sequence Homology, Amino Acid Serine Endopeptidases - analysis Serine Endopeptidases - chemistry Serine Endopeptidases - genetics Static Electricity |
Title | self-inhibited structure of full-length PCSK9 at 1.9 Å reveals structural homology with resistin within the C-terminal domain |
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