My interests over the past 20 years have been directed towards understanding molecular chaperones and how they achieve folding and maturation of proteins. I have particularly concentrated on the Hsp90 chaperone complex. My aims are to understand the molecular details by which Hsp90, and indeed Hsp70, which also plays a role in some Hsp90 complexes, brings about the maturation of proteins (known as client proteins). I have used biochemical, genetic and structural approaches to gain an insight into Hsp90 mechanistic action and regulation of its chaperone cycle. The activation of client proteins by Hsp90 is also dependent on a number of co-chaperones that aid/regulate Hsp90 and its chaperone cycle, to achieve maturation of client proteins. These include Cdc37, Hop/Sti1, Sba1/p23, Aha1, PP5, Xap2, Unc-45, Cyp40, Rar1, Sgt1, FKBP51 and FKBP52 amongst others. My aims are to understand how Hsp90 and such co-chaperones co-operate to bring about the maturation of client proteins.
As Hsp90 is essential for the maturation of a variety of oncogenes my research has been directed towards structure-based drug design against the N-terminal ATP-binding domain of Hsp90. I am also currently collaborating in the development of C-terminal binding inhibitors of Hsp90.
Another aspect of my research involves determining the resistance mechanisms of Hsp90 targeted drugs. I have determined the natural resistance mechanism for radicicol, a macrocyclic antifungal antibiotic, a drug that targets the N-terminal ATP-binding site of Hsp90. I am currently determining the resistance mechanism against another class of Hsp90 inhibitors known as ansamysin antibiotics that include geldanamycin, macbecin and 17-AAG that also target the same N-terminal site.
I have also been active in determining the interaction of co-chaperones that are part of the innate immune system, with Hsp90 and trying to understand the molecular basis by which innate immune complexes help to protect cells from disease.
Recently my interests have turned to Sacsin. I have identified that it possesses homology to the N-terminal and middle domains of Hsp90 (unpublished data). Mutations in Sacsin cause of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). ARSACS is an early onset neurodegenerative disease with high prevalence in the Charlevoix-Saguenay-Lac-Saint-Jean region of Quebec. It is characterized by absent sensory-nerve conduction, reduced motor-nerve velocity and hypermyelination of retinal-nerve fibers. My aim is to understand how sacsin and Hsp90 are structural related and how they are mechanistically related or otherwise.