Mahalakshmi Radhakrishnan

Mahalakshmi Radhakrishnan

Associate Professor
Wellcome Trust / DBT Fellow
Indian Institute of Science Education and Research
Bhopal
India
 (91) 755-2691423
 maha@iiserb.ac.in

Abstract

Peptide–Based Reverse–Mapping of Membrane Protein Aggregation Loci

Mitochondria are the powerhouses of the cell. In the mitochondrial outer membrane, pore-forming β-barrel proteins called voltage-dependent anion channels, VDACs, execute metabolite transport across the membrane, regulate homeostasis, and control apoptosis. Owing to their tendency to oligomerize and aggregate with amyloidogenic proteins, VDACs are increasingly implicated in proteotoxicity and neurodegenerative diseases. However, the intrinsic aggregation sites of VDACs, and the molecular elements that switch a folded functional channel to toxic aggregates, were not known.


Figure

By employing a reverse-mapping strategy involving peptide analogs of VDACs and a heuristic approach involving biophysical, biochemical, in silico analysis, we have now successfully mapped the oligomerization loci of all three human VDAC isoforms. We find that all three VDACs possess similar oligomerization and aggregation hotspots on strands β-5-β11 of its 19-stranded structure. These zones are intrinsically destabilized in all VDACs. Comprehensive thermodynamics and aggregation kinetics measurements using full-length VDAC protein further validates our findings from the peptide-based reverse-mapping approach. Our findings provide molecular insight on how VDACs associate in the cell, opening avenues for developing VDAC-based targeted therapeutics for neurodegenerative aggregates.

Authors

Radhakrishnan Mahalakshmi

Affiliations

Molecular Biophysics Laboratory, Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India

Citations

Lella, M and Mahalakshmi, R. Direct structural annotation of membrane protein aggregation loci using peptide–based reverse–mapping. J. Phys. Chem. Lett. 2018, 9:2967-2971, DOI: 10.1021/acs.jpclett.8b00953
Gupta, A and Mahalakshmi, R. Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3. J. Gen. Physiol. 2019, DOI: 10.1085/jgp.201812272

Lecture Images

Mahalakshmi Radhakrishnan presenting at APS2019 Mahalakshmi Radhakrishnan presenting at APS2019 Mahalakshmi Radhakrishnan presenting at APS2019