Trehalose-cored amphiphiles for membrane protein stabilization: importance of the detergent micelle size in GPCR stability

A novel class of non-chromophoric trehalose-cored amphiphiles was developed and some of the detergents displayed favorable behavior in stabilizing membrane proteins.

Correction: Trehalose-cored amphiphiles for membrane protein stabilization: importance of the detergent micelle size in GPCR stability

Correction for ‘Trehalose-cored amphiphiles for membrane protein stabilization: importance of the detergent micelle size in GPCR stability’ by Manabendra Das et al., Org. Biomol. Chem., 2019, 17, 3249–3257.

A novel lipid-polymer system with unique properties has potential in drug delivery and biotechnology applications

The utility of detergent micelle and bicelle systems has been demonstrated to be a valuable tool for the study of membrane protein interactions and in structural studies. Bicelles are distinguished from micelles in that they contain a lipid bilayer that mimics the plasma membrane of cells making it more native-like than its detergent micelle counter-part. Bicelles are typically comprised of a long-chain phospholipid such as 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and either a short-chain phospholipid, typically 1,2-dihexanoyl-sn-glycero-3-phosphocholine (DHPC), or a bile-salt derivative such as CHAPS or CHAPSO. In solution DMPC and DHPC bicelles assume a discoidal structure comprised of a heterogeneous arrangement where the short-chain lipids gather around the rim of the disk and the long-chain lipids form the flat, bilayer region of the bicelle. Aside from DHPC, CHAPS and CHAPSO few other detergents have reportedly been investigated for their ability to form bicelles with DMPC. In this study, the detergent, C8E5, was used to prepare mixtures with DMPC to determine if it adopts properties similar to DMPC-DHPC bicelles. Mixtures were evaluated using sedimentation equilibrium, 31P-phosphorus NMR, and light scattering and compared to DMPC-DHPC bicelles. Interestingly, mixtures of DMPC and C8E5 assumed a spherical-shaped micellar structure, not the predicted discoidal shape. DMPC-C8E5 mixtures retain interesting properties rendering them particularly advantageous in studies of membrane protein interactions and hold promise as vehicles for drug delivery.

Influenza hemagglutinin membrane anchor

Viruses with membranes fuse them with cellular membranes, to transfer their genomes into cells at the beginning of infection. For Influenza virus, the membrane glycoprotein involved in fusion is the hemagglutinin (HA), the 3D structure of which is known from X-ray crystallographic studies. The soluble ectodomain fragments used in these studies lacked the “membrane anchor” portion of the molecule. Since this region has a role in membrane fusion, we have determined its structure by analyzing the intact, full-length molecule in a detergent micelle, using cryo-EM. We have also compared the structures of full-length HA−detergent micelles with full-length HA−Fab complex detergent micelles, to describe an infectivity-neutralizing monoclonal Fab that binds near the ectodomain membrane anchor junction. We determine a high-resolution HA structure which compares favorably in detail with the structure of the ectodomain seen by X-ray crystallography; we detect, clearly, all five carbohydrate side chains of HA; and we find that the ectodomain is joined to the membrane anchor by flexible, eight-residue-long, linkers. The linkers extend into the detergent micelle to join a central triple-helical structure that is a major component of the membrane anchor.