Research Summary

Molecular Origin of Human VDAC-2 Structure, Function and Regulation:Investigation From Micelles to Bilayers Using Biophysical and Biochemical Approaches

Voltage Dependent Anion Channels, in short, VDACs, are beta-barrel transmembrane proteins in the mitochondrial outer membrane and are crucial players for proper cellular functioning and in the regulatory control of mitochondria-mediated apoptosis. VDACs are implicated in cancer and neurodegenerative diseases including ALS and epilepsy. However, several critical unanswered questions on the molecular basis of VDAC functioning, voltage gating, channel regulation and interaction with pro- and anti-apoptotic agents, particularly in the case of the human VDAC isoform 2, are yet to be addressed.

I combine biochemical and biophysical studies to characterize structural factors and functional elements of human VDACs. In particular, we address three fundamental aspects of hVDAC-2: (i) What are the signature barrel elements that confer structural features to the protein? (ii) What are the functional elements that are necessary for voltage sensing, channel conductance and specificity? (iii) What makes hVDAC-2 anti-apoptotic and hVDAC-1 pro-apoptotic? Most significantly, mapping critical interactions at the molecular level will provide the missing link and make available vital information on control centres between the deduced 19-stranded barrel structure of VDACs and the observed functional dynamics governing cell survival.

Figure Legend: Ribbon diagram of the predicted hVDAC-2 structure depicted along with DPC micelles (grey), highlighting the location of the unusually high number of cysteine residues (yellow spheres) in this barrel.