Structural determinants of the interaction of glycosaminoglycans with GAPDH

AMZEL, M; AVILA, CÉSAR LUIS; BALEANI, MÓNICA ANDREA; GONZÁLEZ LIZARRAGA, MF; PAPY-GARCÍA DULCE; CHEHÍN, ROSANA NIEVES

San Miguel de Tucumán

Congreso; IIILAFeBS, IX IberoAmerican congress of Biophysics, XLV SAB Annual Meeting; 2016

Sociedad Argentina de Biofísica

Glyceraldehide-3-phosphate dehydrogenase (GAPDH) is a glycolytic enzyme that is known as a ?moonlight? protein, due to its diverse functions in addition to its role in energy production. It has been associated to neurodegenerative diseases, but its precise role in these pathologies remains unclear. Previously, we have demonstrated that upon interaction with glycosaminoglycans, such as heparin or heparansulphate, GAPDH is able to reassemble into protofibrils. We have demonstrated the ability of these protofibrils to sequester alpha-synuclein toxic species, a feature that could be exploited for neuroprotection in Parkinson disease. Due to its anticoagulant activity, heparin could not be administered to patients as a mean to increase the formation of GAPDH protofibrils. In this way, understanding the interaction of heparin with GAPDH could aid the search of alternative molecules able to thrust the formation of protofibrils. In this work, we crystallographic structure of GAPDH bound to fondaparinoux, a semisynthetic heparin pentasaccharide. In order to characterize the importance of the interactions established in the crystal, we also study the ability of modified disaccharides to trigger conformational changes and amyloid aggregation of GAPDH. These results unravel the structural determinants necessary to induce the formation of neuroprotective protofibrils and pushes forward the development of a possible therapeutic treatment for Parkinson disease.