title: Binding of human apoA-I[K107del] variant to TG-rich particles: implications for mechanisms underlying hypertriglyceridemia.
abstract: We found earlier that apoA-I variants that induced hypertriglyceridemia (HTG) in mice had increased affinity to TG-rich lipoproteins and thereby impaired their catabolism. Here, we tested whether a naturally occurring human apoA-I mutation, Lys107del, associated with HTG also promotes apoA-I binding to TG-rich particles. We expressed apoA-I[Lys107del] variant in Escherichia coli, studied its binding to TG-rich emulsion particles, and performed a physicochemical characterization of the protein. Compared with WT apoA-I, apoA-I[Lys107del] showed enhanced binding to TG-rich particles, lower stability, and greater exposure of hydrophobic surfaces. The crystal structure of truncated, Δ(185-243), apoA-I suggests that deletion of Lys107 disrupts helix registration and disturbs a stabilizing salt bridge network in the N-terminal helical bundle. To elucidate the structural changes responsible for the altered function of apoA-I[Lys107del], we studied another mutant, apoA-I [Lys107Ala]. Our findings suggest that the registry shift and ensuing disruption of the inter-helical salt bridges in apoA-I[Lys107del] result in destabilization of the helical bundle structure and greater exposure of hydrophobic surfaces. We conclude that the structural changes in the apoA-I[Lys107del] variant facilitate its binding to TG-rich lipoproteins and thus, may reduce their lipolysis and contribute to the development of HTG in carriers of the mutation.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118 Department of Medicine, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gorshkova
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Mei
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118.
authors.forename: David
authors.initials: D
authors.lastname: Atkinson
mesh_terms: D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics; D004655:Emulsions; D006801:Humans; D015228:Hypertriglyceridemia / Q000235:genetics*; D010713:Phosphatidylcholines / Q000737:chemistry; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D017384:Sequence Deletion; D014280:Triglycerides / Q000737:chemistry*
chemical_list: D016632:Apolipoprotein A-I; D004655:Emulsions; D010713:Phosphatidylcholines; D014280:Triglycerides
keywords: apolipoprotein A-I; high plasma triglyceride levels; natural mutation; triglyceride; very low density lipoprotein