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Functional analysis of sites within PCSK9 responsible for hypercholesterolemia

Pandit, Shilpa ; Wisniewski, Doug ; Santoro, Joseph C ; Ha, Sookhee ; Ramakrishnan, Vijayalakshmi ; Cubbon, Rose M ; Cummings, Richard T ; Wright, Samuel D ; Sparrow, Carl P ; Sitlani, Ayesha ; Fisher, Timothy S

Journal of lipid research, June 2008, Vol.49(6), pp.1333-43 [Peer Reviewed Journal]

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  • Title:
    Functional analysis of sites within PCSK9 responsible for hypercholesterolemia
  • Author: Pandit, Shilpa ; Wisniewski, Doug ; Santoro, Joseph C ; Ha, Sookhee ; Ramakrishnan, Vijayalakshmi ; Cubbon, Rose M ; Cummings, Richard T ; Wright, Samuel D ; Sparrow, Carl P ; Sitlani, Ayesha ; Fisher, Timothy S
  • Description: Mutations within proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with dominant forms of familial hypercholesterolemia. PCSK9 binds the LDL receptor (LDLR), and addition of PCSK9 to cells promotes degradation of LDLR. PCSK9 mutant proteins associated with hypercholesterolemia (S127R and D374Y) are more potent in decreasing LDL uptake than is wild-type PCSK9. To better understand the mechanism by which mutations at the Ser127 and Asp374 residues of PCSK9 influence PCSK9 function, a limited vertical scanning mutagenesis was performed at both sites. S127R and S127K proteins were more potent in decreasing LDL uptake than was wild-type PCSK9, and each D374 mutant tested was more potent in reducing LDL uptake when the proteins were added exogenously to cells. The potencies of D374 mutants in lowering LDL uptake correlated with their ability to interact with LDLR in vitro. Combining S127R and D374Y was also found to have an additive effect in enhancing PCSK9's ability to reduce...
  • Is Part Of: Journal of lipid research, June 2008, Vol.49(6), pp.1333-43
  • Identifier: ISSN: 0022-2275 ; PMID: 18354137 Version:1 ; DOI: 10.1194/jlr.M800049-JLR200
  • Subjects: Hypercholesterolemia -- Physiopathology ; Serine Endopeptidases -- Physiology
  • Language: English
  • Source: MEDLINE/PubMed (U.S. National Library of Medicine)

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