TAILIEUCHUNG - Báo cáo khoa học: Investigations on the evolutionary conservation of PCSK9 reveal a functionally important protrusion

Proprotein convertase subtilisin⁄kexin type 9 (PCSK9) interferes with the recycling of low-density lipoprotein (LDL) receptor (LDLR). This leads to LDLR degradation and reduced cellular uptake of plasma LDL. Naturally occurring human PCSK9 loss-of-function mutations are associated with low levels of plasma LDL cholesterol and a reduced risk of coronary heart disease. | ỊFEBS Journal Investigations on the evolutionary conservation of PCSK9 reveal a functionally important protrusion Jamie Cameron1 0ystein L. Holla1 Knut Erik Berge Mari Ann Kulseth1 Trine Ranheim1 Trond P. Leren1 and Jon K. Laerdahl2 1 MedicalGenetics Laboratory Department of MedicalGenetics Rikshospitalet University Hospital Oslo Norway 2 Centre for Molecular Biology and Neuroscience CMBN Institute of MedicalMicrobiology Rikshospitalet University Hospital Oslo Norway Keywords evolutionary conservation LDL cholesterol LDL receptor PCSK9 structural bioinformatics Correspondence J. K. Laerdahl Centre for Molecular Biology and Neuroscience CMBN Institute of MedicalMicrobiology Rikshospitalet University Hospital NO-0027 Oslo Norway Fax 47 22 84 47 82 Tel 47 22 84 47 84 E-mail Received 3 April2008 revised 9 May 2008 accepted 16 June 2008 doi Proprotein convertase subtilisin kexin type 9 PCSK9 interferes with the recycling of low-density lipoprotein LDL receptor LDLR . This leads to LDLR degradation and reduced cellular uptake of plasma LDL. Naturally occurring human PCSK9 loss-of-function mutations are associated with low levels of plasma LDL cholesterol and a reduced risk of coronary heart disease. PCSK9 gain-of-function mutations result in lower LDL clearance and increased risk of atherosclerosis. The exact mechanism by which PCSK9 disrupts the normal recycling of LDLR remains to be determined. In this study we have assembled homologs of human PCSK9 from 20 vertebrates a cephalochordate and mollusks in order to search for conserved regions of PCSK9 that may be important for the PCSK9-mediated degradation of LDLR. We found a large conserved protrusion on the surface of the PCSK9 catalytic domain and have performed site-directed mutagenesis experiments for 13 residues on this protrusion. A cluster of residues that is important for the degradation of LDLR by PCSK9 was identified. Another cluster of residues at .

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