Source:http://linkedlifedata.com/resource/pubmed/id/19001363
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2
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| pubmed:dateCreated |
2009-1-5
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| pubmed:databankReference | |
| pubmed:abstractText |
PCSK9 regulates low density lipoprotein receptor (LDLR) levels and consequently is a target for the prevention of atherosclerosis and coronary heart disease. Here we studied the interaction, of LDLR EGF(A/AB) repeats with PCSK9. We show that PCSK9 binds the EGF(AB) repeats in a pH-dependent manner. Although the PCSK9 C-terminal domain is not involved in LDLR binding, PCSK9 autocleavage is required. Moreover, we report the x-ray structure of the PCSK9DeltaC-EGF(AB) complex at neutral pH. Compared with the low pH PCSK9-EGF(A) structure, the new structure revealed rearrangement of the EGF(A) His-306 side chain and disruption of the salt bridge with PCSK9 Asp-374, thus suggesting the basis for enhanced interaction at low pH. In addition, the structure of PCSK9DeltaC bound to EGF(AB)(H306Y), a mutant associated with familial hypercholesterolemia (FH), reveals that the Tyr-306 side chain forms a hydrogen bond with PCSK9 Asp-374, thus mimicking His-306 in the low pH conformation. Consistently, Tyr-306 confers increased affinity for PCSK9. Importantly, we found that although the EGF(AB)(H306Y)-PCSK9 interaction is pH-independent, LDLR(H306Y) binds PCSK9 50-fold better at low pH, suggesting that factors other than His-306 contribute to the pH dependence of PCSK9-LDLR binding. Further, we determined the structures of EGF(AB) bound to PCSK9DeltaC containing the FH-associated D374Y and D374H mutations, revealing additional interactions with EGF(A) mediated by Tyr-374/His-374 and providing a rationale for their disease phenotypes. Finally, we report the inhibitory properties of EGF repeats in a cellular assay measuring LDL uptake.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jan
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| pubmed:issn |
0021-9258
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| pubmed:author |
pubmed-author:BaysarowichJenniferJ,
pubmed-author:BottomleyMatthew JMJ,
pubmed-author:CalzettaAlessandraA,
pubmed-author:CarfíAndreaA,
pubmed-author:CirilloAgostinoA,
pubmed-author:CubbonRose MRM,
pubmed-author:CummingsRichard TRT,
pubmed-author:De FrancescoRaffaeleR,
pubmed-author:FisherTimothy STS,
pubmed-author:Lo SurdoPaolaP,
pubmed-author:LoHH,
pubmed-author:NotoAlessiaA,
pubmed-author:OrsattiLauraL,
pubmed-author:RuggeriLionelloL,
pubmed-author:SantoroJoseph CJC,
pubmed-author:SitlaniAyeshaA,
pubmed-author:SparrowCarl PCP,
pubmed-author:TalamoFabioF
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| pubmed:issnType |
Print
|
| pubmed:day |
9
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| pubmed:volume |
284
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1313-23
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| pubmed:meshHeading |
pubmed-meshheading:19001363-Amino Acid Sequence,
pubmed-meshheading:19001363-Cell Line,
pubmed-meshheading:19001363-Crystallography, X-Ray,
pubmed-meshheading:19001363-Humans,
pubmed-meshheading:19001363-Hyperlipoproteinemia Type II,
pubmed-meshheading:19001363-Models, Molecular,
pubmed-meshheading:19001363-Molecular Sequence Data,
pubmed-meshheading:19001363-Mutation,
pubmed-meshheading:19001363-Protein Binding,
pubmed-meshheading:19001363-Protein Structure, Quaternary,
pubmed-meshheading:19001363-Protein Structure, Tertiary,
pubmed-meshheading:19001363-Receptors, LDL,
pubmed-meshheading:19001363-Serine Endopeptidases
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| pubmed:year |
2009
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| pubmed:articleTitle |
Structural and biochemical characterization of the wild type PCSK9-EGF(AB) complex and natural familial hypercholesterolemia mutants.
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| pubmed:affiliation |
Department of Biochemistry, Istituto di Ricerca di Biologia Molecolare "P. Angeletti", Via Pontina Km 30.600, 00040 Pomezia (Rome), Italy. matthew_bottomley@merck.com
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| pubmed:publicationType |
Journal Article
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