title: Mechanistic implications for LDL receptor degradation from the PCSK9/LDLR structure at neutral pH.
abstract: The protein PCSK9 (proprotein convertase subtilisin/kexin type 9) is a key regulator of low-density lipoprotein receptor (LDLR) levels and cardiovascular health. We have determined the crystal structure of LDLR bound to PCSK9 at neutral pH. The structure shows LDLR in a new extended conformation. The PCSK9 C-terminal domain is solvent exposed, enabling cofactor binding, whereas the catalytic domain and prodomain interact with LDLR epidermal growth factor(A) and β-propeller domains, respectively. Thus, PCSK9 seems to hold LDLR in an extended conformation and to interfere with conformational rearrangements required for LDLR recycling.
authors.affiliation: Department of Biochemistry and Molecular Biology, IRBM P. Angeletti, Via Pontina Km 30.600, Pomezia, Rome I-00040, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lo Surdo
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bottomley
authors.forename: Alessandra
authors.initials: A
authors.lastname: Calzetta
authors.forename: Ethan C
authors.initials: EC
authors.lastname: Settembre
authors.forename: Agostino
authors.initials: A
authors.lastname: Cirillo
authors.forename: Shilpa
authors.initials: S
authors.lastname: Pandit
authors.forename: Yan G
authors.initials: YG
authors.lastname: Ni
authors.forename: Brian
authors.initials: B
authors.lastname: Hubbard
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: Andrea
authors.initials: A
authors.lastname: Carfí
mesh_terms: D015536:Down-Regulation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011973:Receptors, LDL / Q000737:chemistry* / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
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