Featured Article - January 2015
Short description: A sliding hinge in gp41 promotes HIV membrane fusion and viral infection.
To enter a host cell, human immunodeficiency virus type 1 (HIV-1) must fuse its viral membrane with the host cell membrane. It accomplishes this feat via the envelope glycoprotein gp160—a trimer of gp120/gp41 heterodimers. Gp120 binds to host cell receptors, which induces conformational changes in gp41 that bring the two membranes together.
The membrane proximal external region (MPER) of gp41 is highly conserved across HIV subtypes and is essential for membrane fusion. Reinherz and colleagues (PSI MPSbyNMR) have structurally characterized this region using nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) to better understand its role in membrane fusion and viral infectivity.
The authors solved the NMR structures of three wild-type MPER peptides from different HIV subtypes in dodecylphosphocholine micelles (PDB 2ME2, 2ME3, 2ME4). Consistent with a previous MPER structure, the peptides adopted a helix-hinge-helix motif embedded in the viral membrane. They focused on the hinge region, which is the target of several broadly neutralizing antibodies.
Structures of antibody-bound MPER peptides showed that the hinge region can slide along the peptide. In some structures, the side chain of residue 671 acted as an N-terminal cap for the C-terminal helix; in others, residue 674 acted as the cap.
To demonstrate the importance of these residues, the authors mutated the pair to alanine, which lacks the ability to form an N-terminal cap. The double mutant could not support membrane fusion and viral infectivity, and its NMR structure (PDB 2ME1) showed an extended N-terminal helix and shortened C-terminal helix. In addition, the region between the two helices was no longer a hinge, but an elongated unstructured linker. EPR depth measurements revealed that the alanine double mutant MPER sits lower within the membrane, with fewer solvent-exposed residues than wild-type sequences.
The authors speculated that the hinge could act as a pivot point for gp41. The flexibility afforded by the ability of the hinge to slide may allow the protein to accommodate the changing curvature of the membrane as it fuses. In addition, varying the position of the hinge flips the orientation of key aromatic side chains, which may facilitate lipid mixing between the two membranes.
Z. Y. Sun et al. Disruption of helix-capping residues 671 and 674 reveals a role in HIV-1 entry for a specialized hinge segment of the membrane proximal external region of gp41.
J Mol Biol. 426, 1095-1108 (2014). doi:10.1016/j.jmb.2013.09.030