Prediction of heparin binding sites on GAPDH

TORRES BUGEAU, CLARISA; AVILA, CÉSAR; CHEHÍN ROSANA

Córdoba

Congreso; 2do Congreso Argentino de Bioinformática y Biología Computacional; 2011

Sociedad Argentina de Bioinformática y Biología Computacional

Background Lewy bodies and Lewy neuritis, neuropathological characteristics of Parkinson’s disease, are mainly made by filamentous assemblies of α-synuclein. However, glycosaminoglycans (GAGs) along with other proteins like tau and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) are routinely found associated with these amyloid deposits. It has been suggested that GAPDH:GAGs interaction may play a key role in the formation of Lewy´s bodies and it must be considered as main actors in Parkinson’s disease and other diseases involving α-synuclein aggregates. Indeed, it has been demonstrated that heparin is able to trigger the GAPDH amyloid fibrils formation which in turn can also induce a cross-seeding effect on the fibrillation of α-synuclein. Results Herein, we conducted an in silico search for heparin binding sites on GAPDH aided with the program AutoDock. Because of the high charge density and the weak surface complementarity of the sulfated sugar chain, prediction of heparin binding sites on protein presents a challenging task for computational docking. We developed a protocol that was able to successfully reproduce heparin binding sites on thrombin light chain and acidic and basic fibroblast growth factor, three proteins for which structures of their complexes with heparin are available. This procedure was then used to predict the heparin binding site on GAPDH. The results indicate that positively charged residues play a critical role in the interaction with the sulfate and carboxylate groups of the GAG chain. Conclusions Given the importance of protein-glycosaminoglycan interactions, the identification of protein sequences that interact specifically with heparin could shed light on the mechanism of protein amyloidogenesis.