LYSINE 107 IS CRITICAL FOR LIPID-FREE APOLIPOPROTEIN A-I TERTIARY CONFORMATION

DÍAZ LUDOVICO IVO; SHIMPI BEDI; JAMIE MORRIS; SCOTT E. STREET; GARDA, HORACIO A.; ESMOND GEH; GONZALEZ MARINA CECILIA; W. SEAN DAVIDSON; JOHN T. MELCHIOR

La Plata

Congreso; XLIX Reunión anual de la Sociedad Argentina de Biofísica (SAB); 2021

Sociedad Argentina de Biofísica SAB

Apolipoprotein A1 (APOA1) is the primarily protein component of high-density lipoproteins (HDLs) which play important roles in metabolic disorders such as obesity, diabetes, and cardiovascular disease (CVD). Situated at the water-lipid interface, APOA1 adopts a variety of structural conformations on the lipid surface to accommodate docking with various enzymes, lipid transfer proteins, and cell surface receptors that remodel HDL during its lifespan. In this way, APOA1 acts as a master regulator of both HDL composition and function. The deletion mutant Lys107del (∆K107) is a natural variant of APOA1 that occurs in humans which is associated with hypertriglyceridemia and accelerated atherosclerosis and CVD. The purpose of these studies was to determine if structural differences exists in the ∆K107 APOA1 molecule that could explain the observed alteration in lipid metabolism in carriers of ∆K107 variant. Using a combination of high-resolution size exclusion chromatography, chemical cross-linking, and liquid chromatography-mass spectrometry we performed deep structural analysis on WT APOA1 and ∆K107 APOA1. We found the absence of Lys 107 severely impeded the ability of APOA1 to self-associate into higher order oligomers. Differences in the cross-linking pattern between APOA1 and ∆K107 APOA1 indicate that deletion of Lys 107 severely disrupted intermolecular interactions between APOA1 molecules in the N-terminal region of the molecule. Given that APOA1 self-association is thought to be a critical step in HDL biogenesis, our findings suggest the absence of Lys 107 results in a structural change that could alter HDL formation and/or function which may underlie the dyslipidemia observed in ∆K107 carriers.