Sequence-specific conformational dynamics of model transmembrane domains determines their membrane fusogenic function.
The transmembrane domains of fusion proteins are known to be functionally important and display an overabundance of helix-destabilizing Ile and Val residues. In an effort to systematically study the relationship of fusogenicity and helix stability, we previously designed LV peptides, a low-complexity model system whose hydrophobic core consists of Leu and Val residues at different ratios. The ability of LV peptides to fuse membranes increases with the content of helix-destabilizing residues. Here, we monitored the kinetics of amide deuterium/hydrogen exchange of LV-peptide helices to probe their conformational dynamics. The kinetics indeed increases strongly with the content of helix-destabilizing residues and is likely to reflect local fluctuations of the helix backbones as all peptides exhibit uncorrelated exchange and contain subpopulations of amide deuterium atoms that exchange with different velocities. Interestingly, helices whose amide deuterium atoms are shifted from slower to faster subpopulations are more fusogenic. Novel peptide variants in which Val residues are concentrated at peripheral or central domains of the hydrophobic core were designed to map functionally relevant helix subdomains. Their structural and functional analysis suggests that dynamic domains close to the helix termini are more relevant for fusogenicity than central domains but cooperate with the latter to achieve strong fusogenicity.
Poschner
Bernhard C
BC
Lehrstuhl für Chemie der Biopolymere, Technische Universität München, Weihenstephaner Berg 3, 85354 Freising, Germany.
Quint
Stefan
S
Hofmann
Mathias W
MW
Langosch
Dieter
D
D003903:Deuterium / Q000378:metabolism; D006859:Hydrogen / Q000378:metabolism; D007700:Kinetics; D008561:Membrane Fusion; D050576:Membrane Fusion Proteins / Q000737:chemistry* / Q000378:metabolism*; D008566:Membranes; D011487:Protein Conformation
D050576:Membrane Fusion Proteins; D006859:Hydrogen; D003903:Deuterium