Fellows' research: Role of protein-lipid mismatch in biological membranes
21 Jan 2019
Dr R Mahalakshmi, Intermediate Fellow
Indian Institute of Science Education and Research, Bhopal
Our recently published study identifies, for the first time, the importance of protein-lipid mismatch for stabilizing a transmembrane protein barrel of the mitochondrial outer membrane that is indispensable for cell survival.
Membranes of the cell possess a dynamic phospholipid bilayer, harboring membrane proteins that carry out functions vital for cell survival. These proteins are generally helical; however, transmembrane barrel proteins are present in the outer mitochondrial membrane (OMM). Voltage-dependent anion channels (VDACs) are such mitochondrial outer membrane proteins that form pores for the transport of metabolites and ions across the OMM. A functional VDAC is vital for the survival of any cell. VDAC, like other membrane proteins, requires an optimal membrane environment to function. Yet, it is not known how the physico-chemical characteristics of the membrane bilayer regulate this most important metabolite flux protein. Considering the increase in cancer and neurodegeneration and the link between VDAC and the incidence of these diseases, identifying molecular factors that affect VDAC regulation has become a priority.
To study the effect of the most abundant mitochondrial membrane lipids (phosphocholine) on VDAC, we used a combinatorial approach involving biophysical measurements of protein stability with all-atom molecular dynamics simulations. With this combinatorial approach, we show for the first time that a negative mismatch between the membrane and the VDAC channel is required for stability of the protein in the OMM, and for its function as a metabolite flux channel. We also show that altering the bilayer thickness by increasing or decreasing the hydrocarbon chain length of the phosphocholine lipid, or the presence of cholesterol, lower the stability of VDAC. Our findings provide the first insight of how cells use an elegant and simple mechanism of altering the bilayer physical properties to regulate the function and turnover of VDACs in the OMM. We also establish that bilayer-protein mismatch versus match can switch the cell between homeostasis and cell death, opening avenues to understanding how the lipid membrane is linked to disease states including cancer and neurodegeneration.
Image notes: Stable (green) versus destabilized (red) human VDAC2 barrels, as modulated by the bilayer thickness decided by the 14-carbon DMPC, 16-carbon DPPC, and presence of cholesterol.
Hydrophobic mismatch modulates stability and plasticity of human mitochondrial VDAC2. Shashank RanjanSrivastava, Punit Zadafiya, Radhakrishnan Mahalakshmi. Biophysical Journal. December 2018