Natural variants of human apolipoprotein A-I: structural perturbations associated to protein misfolding

GADDI, GM; TRICERRI, MA; FINARELLI; GS; SCHINELLA, G; PRIETO; ED; RAMELLA; NA; CORTEZ, MF; ROSU; SA; GISONNO, R

MEXICO DF

Congreso; VI LATIN AMERICAN PROTEIN SOCIETY MEETING; 2019

LAPS

Since the early description of different human apolipoprotein A-I variantsassociated to amyloidosis, the reason that determines its deposition inducing organfailure has been under research. To shed light into the events associated to proteinaggregation, we studied the effect of the structural perturbations induced by thereplacement of a Leucine in position 60 by an Arginine as it occurs in the naturalamyloidogenic variant (L60R). Circular dichroism, intrinsic fluorescence measurementsand proteolysis analysis indicate that L60R is more unstable, more sensitive to cleavageand the N terminus more disorganized than the protein with the native sequence (Wt).A higher tendency to aggregate is also detected when incubated L60R at physiologicalpH. In addition, the small structural rearrangement observed leads to the release oftumor necrosis factor a and interleukin-1b from a model of macrophages. In spite of that,the conformational stability of the dimer and the binding to lipids is preserved.Our results strongly suggest that the chronic disease may be a consequence of the lossin the native conformation which elicits the release of protein conformations that couldbe either cytotoxic or precursors of amyloid conformations