Fellows' research : Living on the edge - New insights into cell membrane structure & energetics
29 Nov 2018
Dr. R. Mahalakshmi, Intermediate Fellow
Our recently published research in the journal Biochemistry provides new insights into why one of the most versatile amino acids, histidine, is less abundant in specific regions in the cell membrane. This information is critical for computational prediction of protein structures which finds its application in drug design.
All cells have a semi-porous outer plasma membrane made up of layers of lipids and proteins that protects it from the external environment, control movement of nutrients, drugs and even pathogenic microbes. Proteins present in the membrane play a key role in this regulation. These membrane proteins have a unique architecture that allows the selection of amino acid residues with specific physical and chemical properties at different positions of their structure.
Defects in the structure of these membrane proteins can destabilise the cell membrane thereby affecting its normal biological function. Since, cell membrane plays a critical role in various biological and physiological processes, which also makes it an important drug target, it is imperative to investigate factors that regulate its structural and thermodynamic stability.
The interface region of the membrane proteins is of utmost interest due to their contribution to the stability of cell membrane. Residues at the interface act as mediating agents between the water-loving exterior (hydrophilic) and water-hating (hydrophobic) interior regions in the membrane. Aromatic amino acids contain both hydrophobic as well as hydrophilic (amphipathic) parts and are, therefore, favoured at these interfaces.
Of the 20 widely prevalent amino acids, four residues possess aromatic side chains: phenylalanine, tyrosine, tryptophan, and histidine. Interestingly, histidine occurs infrequently at the membrane interface, particularly in transmembrane β-barrel proteins. These β-barrel proteins are important for cargo transport and relaying signals through the membrane.
In our recently published study, we examined the energetic contribution of an interface histidine to the stability of a model transmembrane β-barrel. We found that the presence of histidine at the interface lowers the stability of the protein considerably. Additionally, we examined whether the preceding residue can rescue the destabilizing effect of an interface histidine. We established a universal destabilizing effect of histidine irrespective of the flanking residue. In addition, a few residues also alter the folding equilibrium of the protein from a two-state to a three-state folding pathway.
Our research provides a thermodynamic explanation for why histidines are not found abundantly at membrane protein interfaces. Our findings are of immense use in explaining the evolutionary selection of specific physico-chemical characteristics in membrane proteins, and provide the foundation for de novo protein design.
Salvaging the Thermodynamic Destabilization of Interface Histidine in Transmembrane β-Barrels. Bharat Ramasubramanian Iyer, Pallavi Vijay Vetal, Henna Noordeen, Punit Zadafiya, and Radhakrishnan Mahalakshmi. Biochemistry. October 2018. (in press)
Banner image credit: Dr.R. Mahalakshmi, IISER, Bhopal