7ANQ

Complete PCSK9 C-ter domain in complex with VHH P1.40

Replaces:  6F5G

Summary for 7ANQ

• Entry DOI: 10.2210/pdb7anq/pdb
• Descriptor: Proprotein convertase subtilisin/kexin type 9, VHH P1.40 minibody anti-Cter PCSK9, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: pcsk9, vhh p1.40, complex, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 39524.16

Authors

Ciccone, L.,Legrand, P.,Stura, E.A.,Dive, V.,Seidahn, N.G.,Fruchart Gaillard, C. (deposition date: 2020-10-12, release date: 2021-10-20, Last modification date: 2024-11-20)

Primary citation

Fruchart Gaillard, C.,Ouadda, A.B.D.,Ciccone, L.,Girard, E.,Mikaeeli, S.,Evagelidis, A.,Le Devehat, M.,Susan-Resiga, D.,Lajeunesse, E.C.,Nozach, H.,Ramos, O.H.P.,Thureau, A.,Legrand, P.,Prat, A.,Dive, V.,Seidah, N.G.
Molecular interactions of PCSK9 with an inhibitory nanobody, CAP1 and HLA-C: Functional regulation of LDLR levels.
Mol Metab, 67:101662-101662, 2022

PubMed Abstract: The liver-derived circulating PCSK9 enhances the degradation of the LDL receptor (LDLR) in endosomes/lysosomes. PCSK9 inhibition or silencing is presently used in clinics worldwide to reduce LDL-cholesterol, resulting in lower incidence of cardiovascular disease and possibly cancer/metastasis. The mechanism by which the PCSK9-LDLR complex is sorted to degradation compartments is not fully understood. We previously suggested that out of the three M1, M2 and M3 subdomains of the C-terminal Cys/His-rich-domain (CHRD) of PCSK9, only M2 is critical for the activity of extracellular of PCSK9 on cell surface LDLR. This likely implicates the binding of M2 to an unknown membrane-associated "protein X" that would escort the complex to endosomes/lysosomes for degradation. We reported that a nanobody P1.40 binds the M1 and M3 domains of the CHRD and inhibits the function of PCSK9. It was also reported that the cytosolic adenylyl cyclase-associated protein 1 (CAP1) could bind M1 and M3 subdomains and enhance the activity of PCSK9. In this study, we determined the 3-dimensional structure of the CHRD-P1.40 complex to understand the intricate interplay between P1.40, CAP1 and PCSK9 and how they regulate LDLR degradation.

PubMed: 36566984
DOI: 10.1016/j.molmet.2022.101662

Experimental method

X-RAY DIFFRACTION (2.2 Å)