Congratulations to lab alumns Dr. Abshishek Mandal and Dr. Jennifer Boatz, as well as our collaborators in the USA and Spain! A new collaborative paper on mitochondrial protein-lipid interactions has just been published in the journal PNAS. In this multidisciplinary work we studied how the protein Drp1 binds the special mitochondrial lipid cardiolipin in order to do its job managing the proper fission of mitochondrial membrane. Our collaborator Rajesh Ramachandran (at Case Western) coordinated a wide array of experimental and computational approaches to determine how Drp1’s “variable domain” (VD) binds cardiolipin. Along the way, two apparent CL-binding motifs were detected, which are seemingly shared by other CL-binding proteins. Their mutation disrupts CL binding and also the proper management of mitochondrial morphology, pointing to the importance of CL-based signals and interactions in this vital cellular process.
Experimentally, our group contributed various solid-state NMR measurements of the lipids, with which we probe the specificity of the interactions and also observe how the protein modulates the lipid bilayer itself. Moreover, we were involved in the sequence/structure analysis: sequence analysis of the “disordered” VD domain pinpointed those parts of the structure most likely to engage in lipid-driven folding upon membrane binding. The “MoRF” motifs (“molecular recognition features”) indeed appear to be involved in CL binding, based on NMR and mutational studies. In Drp1 they are intimately involved in a folding transition of the VD domain upon membrane binding. It will be interesting to see how widespread these CL-binding motifs (CBMs) are in other CL-binding proteins.
Reference:
[1] Mahajan M, Bharambe N, Shang Y, Lu B, Mandal A, Madan Mohan P, et al. NMR identification of a conserved Drp1 cardiolipin-binding motif essential for stress-induced mitochondrial fission. Proc Natl Acad Sci USA2021;118:e2023079118. https://doi.org/10.1073/pnas.2023079118.