Structure-function relationships in apolipoprotein A-I mutants associated with amyloidosis

ROSU, S. A.; RAMELLA, N.; SCHINELLA, G; RIOS, J. L.; ANDUJAR, I.; RIMOLDI. O. J.; TRICERRI, M. A.

Río de Janeiro

Simposio; IX International Symposium on Familial Amyloidotic Polyneuropathy; 2013

Unversidad Federal de Río de Janeiro

Amyloidosis induced by Human apolipoprotein A-I (apoA-I) represent a broad range of clinical manifestations, depending on the protein variant which is involved. Senile non hereditary amylodosis, is characterized by deposits of protein with the wild type sequence (WT) in atherosclerotic plaques, thus opening the hypothesis that a chronic inflammatory micro environment could elicit protein misfolding and or loss of function. But in addition, more than fifteen single point mutants of this protein are associated with amylodosis in patients, affecting different organs and with different severity. In order to get insight into the mechanism inducing protein misfolding, we constructed three natural amyloidogenic variants (Arg173Pro, Gly26Arg and Lys107-0), and compared their behavior with WT. The three mutants are less stable than WT at physiological pH, and show a non cooperative unfolding. However only Arg173Pro and Lys107-0 have a stronger tendency to aggregate under this condition. Arg173Pro shows also higher tendency to bind to heparin under mild acidic pH and in the presence of small amounts of dodecyl sodium sulfate. Instead Gly26Arg but not Lys107-0 enhances macrophages activation, which could be a clue mechanism to perpetuate a pro-inflammatory micro environment. Results indicate that subtle structural changes are required to induce protein pathogenicity, however this is not only related to protein instability but to the specific activation of cellular pathways that could enhance their toxicity under specific conditions as well.