Structure and Functionality of Molecular chaperones

Molecular chaperones are indispensable cellular components able to prevent off-pathway folding events and to refold misfolded proteins. In fact, molecular chaperones play a strategical role in the Protein Quality Control machinery and aging-associated failure. This makes them putative therapeutic agents for fighting neurodegenerative diseases associated with aggregation of misfolded proteins. We are currently studying the relation between structure stability (i.e. oligomeric status and post-translational modifications) and mechanisms of action in health and disease in the cases of Hsp60 and TRiC (CCT). The two molecules have similar multimeric structure but different mechanism of action. Hsp60 works in presence of ATP and a co-chaperon (Hsp10) that acts as a lid to regulate the substrate egress. However, we have observed that it is capable of exerting a stabilizing action on beta-amiloid peptide aggregation that appears less or more effective depending on the degree of multimeric association. CCT exerts its action in presence of ATP as well, but it doesn’t require the presence of a co-chaperon. A heritable CCT5 subunit mutation causes a profound sensory neuropathy in humans. A convenient model system to elucidate the impact of a pathogenic mutation on the intrinsic properties and on the chaperoning functions of the human TRiC/CCT5 had been recently proposed by Prof.’s Macario group. Now, we are working on the quantitative estimation of the loss of structural stability in the hexadecamer containing the pathogenic mutation by means differential scanning calorimetry (DSC) and isothermal titration calorimetry (ITC).

Members:
Celeste Caruso Bavisotto
Rosa Passantino
Pier Luigi San Biagio
Silvia Vilasi