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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
6
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pubmed:dateCreated |
2008-2-14
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pubmed:databankReference |
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pubmed:abstractText |
Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-11478865,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-11799113,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-12459547,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-12730697,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-12788922,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-1301956,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-14675545,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-14993666,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15299374,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15299926,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15358785,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15385538,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15494314,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15571716,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15572765,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15654334,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-15950875,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-16554528,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-16909389,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-16912035,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17080197,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17215125,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17435765,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17452316,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17461796,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17493938,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17495605,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17537735,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17608623,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-17804797,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-18039658,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-1872803,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-3494949,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-6327078,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-7606779,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-8129949,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-8876162,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-9599222,
http://linkedlifedata.com/resource/pubmed/commentcorrection/18250299-9757107
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1091-6490
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
12
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pubmed:volume |
105
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1820-5
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pubmed:dateRevised |
2009-11-18
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pubmed:meshHeading |
pubmed-meshheading:18250299-Binding Sites,
pubmed-meshheading:18250299-Cell Line,
pubmed-meshheading:18250299-Epidermal Growth Factor,
pubmed-meshheading:18250299-Humans,
pubmed-meshheading:18250299-Hydrogen-Ion Concentration,
pubmed-meshheading:18250299-Lipoproteins, LDL,
pubmed-meshheading:18250299-Models, Molecular,
pubmed-meshheading:18250299-Mutagenesis, Site-Directed,
pubmed-meshheading:18250299-Protein Binding,
pubmed-meshheading:18250299-Protein Conformation,
pubmed-meshheading:18250299-Receptors, LDL,
pubmed-meshheading:18250299-Serine Endopeptidases
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pubmed:year |
2008
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pubmed:articleTitle |
Molecular basis for LDL receptor recognition by PCSK9.
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pubmed:affiliation |
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9050, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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