“Determining the impact of protein-protein interactions on Transglutaminase 2 activity”

Tonya N. Zeczycki, PhD

Assistant Professor

Department of Biochemistry and Molecular Biology and the East Carolina Diabetes and Obesity Institute

East Carolina Heart Institute

Host: Nicholas R. Silvaggi

ABSTRACT

In progressive neurodegenerative diseases, the underlying cause of cognitive decline and dementia is the ab-normal accumulation of toxic protein aggregates composed of α-synuclein, tau and β-amyloid. The Ca2+-dependent, post-translational modification of these proteins by transglutaminase 2 (TG2) results in modified proteins with an increase propensity for self-aggregation. While the molecular level mechanisms by which Ca2+ allosterically regulates TG2 activity could be key to differentiating between biological and pathological activity, details regarding the allosteric mechanism remains a fundamental gap in our knowledge In contrast to the currently accepted mechanism of regulation, our data shows that there are two allosteric events required for TG2 activation, namely a substrate-induced conformational change upon α-synuclein binding prior to a second, Ca2+-induced conformational change necessary for catalytic turnover. Protein-protein interactions between the substrate and TG2 actually sensitize the enzyme to Ca2+ activation, suggesting a novel mechanism for allosteric regulation.