First eight residues of apolipoprotein A-I mediate the C-terminus control of helical bundle unfolding and its lipidation


Autoři: Gregory Brubaker aff001;  Shuhui W. Lorkowski aff001;  Kailash Gulshan aff001;  Stanley L. Hazen aff001;  Valentin Gogonea aff001;  Jonathan D. Smith aff001
Působiště autorů: Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, Ohio, United States of America aff001;  Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, United States of America aff002;  Department of Chemistry, Cleveland State University, Cleveland, Ohio, United States of America aff003
Vyšlo v časopise: PLoS ONE 15(1)
Kategorie: Research Article
doi: 10.1371/journal.pone.0221915

Souhrn

The crystal structure of a C-terminal deletion of apolipoprotein A-I (apoA1) shows a large helical bundle structure in the amino half of the protein, from residues 8 to 115. Using site directed mutagenesis, guanidine or thermal denaturation, cell free liposome clearance, and cellular ABCA1-mediated cholesterol efflux assays, we demonstrate that apoA1 lipidation can occur when the thermodynamic barrier to this bundle unfolding is lowered. The absence of the C-terminus renders the bundle harder to unfold resulting in loss of apoA1 lipidation that can be reversed by point mutations, such as Trp8Ala, and by truncations as short as 8 residues in the amino terminus, both of which facilitate helical bundle unfolding. Locking the bundle via a disulfide bond leads to loss of apoA1 lipidation. We propose a model in which the C-terminus acts on the N-terminus to destabilize this helical bundle. Upon lipid binding to the C-terminus, Trp8 is displaced from its interaction with Phe57, Arg61, Leu64, Val67, Phe71, and Trp72 to destabilize the bundle. However, when the C-terminus is deleted, Trp8 cannot be displaced, the bundle cannot unfold, and apoA1 cannot be lipidated.

Klíčová slova:

Crystal structure – Disulfide bonds – Cholesterol – Lipid structure – Lipids – Liposomes – Point mutation – Guanidines


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