Structural and Functional Analysis of hARV1 Lipid Binding

Author(s)

Jamie Francisco

Date Approved

4-2014

Document Type

Thesis

Degree Name

Master of Science in Molecular Pathology and Immunology

Department

Molecular Biology

College

Graduate School of Biomedical Sciences

First Advisor

Salvatore Caradonna, PhD

Committee Member 1

Joseph Nickels, PhD

Committee Member 2

Jason Trama, PhD

Subject(s)

Cardiovascular Diseases; Membrane Lipids; Lipid-Linked Proteins

Disciplines

Cell Biology | Medicine and Health Sciences | Molecular Biology | Molecular Genetics

Abstract

Cardiovascular disease (CVD) has the highest mortality rate worldwide and is considered epidemic in the United States. Statins as the primary and almost sole method of treatment for cholesterol-related CVD, but they have limitations. Proper sterol transport is needed to maintain normal blood lipid levels. Studies have shown that misregulation of lipid trafficking aids in the progression of CVD and in the activation of the unfolded protein response (UPR). Misregulation of lipid and sterol homeostasis also results in the loss of lipid rafts, known cellular signaling hubs and major components of ER associated membrane contact sites. Arv1 is a highly conserved 3 transmembrane putative lipid/sterol transporter. Loss of human or yeast Arv1 alters sterol, sphingolipid, and phospholpid biosynthesis and metabolism, as well as highly activating the unfolded protein response. In an effort to understand Arv1 function, a structure/function analysis was carried out to determine if Arv1 binds lipids, and if so, what lipids it does bind? Moreover, domains within Arv1 needed for any lipid binding were defined. We demonstrate the hArv1 binds the anionic lipids, phosphatidic acid, phosphatidylserine, and cardiolipin, as well as, cholesterol. We provide evidence that Arv1 also binds signaling phosphoinostitides. These results, taken with the phenotypic data regarding loss of Arv1, allude to a role for Arv1 in overall lipid and sterol trafficking.

Recommended Citation

Francisco, Jamie, "Structural and Functional Analysis of hARV1 Lipid Binding" (2014). Graduate School of Biomedical Sciences Theses and Dissertations. 69.
https://rdw.rowan.edu/gsbs_etd/69