Acid-induced movements in the glycoprotein shell of an alphavirus turn the spikes into membrane fusion mode.
In the icosahedral (T = 4) Semliki Forest virus, the envelope protomers, i.e. E1-E2 heterodimers, make one-to-one interactions with capsid proteins below the viral lipid bilayer, transverse the membrane and form an external glycoprotein shell with projections. The shell is organized by protomer domains interacting as hexamers and pentamers around shell openings at icosahedral 2- and 5-fold axes, respectively, and the projections by other domains associating as trimers at 3- and quasi 3-fold axes. We show here, using cryo- electron microscopy, that low pH, as occurs in the endosomes during virus uptake, results in the relaxation of protomer interactions around the 2- and the 5-fold axes in the shell, and movement of protomers towards 3- and quasi 3-fold axes in a way that reciprocally relocates their putative E1 and E2 domains. This seemed to be facilitated by a trimerization of transmembrane segments at the same axes. The alterations observed help to explain several key features of the spike-mediated membrane fusion reaction, including shell dissolution, heterodimer dissociation, fusion peptide exposure and E1 homotrimerization.
Karolinska Institute, Department of Biosciences, S-141 57 Huddinge, Sweden.
Lars
L
Haag
Henrik
H
Garoff
Li
L
Xing
Lena
L
Hammar
Sin-Tau
ST
Kan
R Holland
RH
Cheng
D017738:Alkanesulfonic Acids / Q000494:pharmacology*; D000818:Animals; D002213:Capsid / Q000187:drug effects / Q000648:ultrastructure; D002460:Cell Line / Q000821:virology; D006224:Cricetinae; D020285:Cryoelectron Microscopy; D003588:Cytopathogenic Effect, Viral; D019281:Dimerization; D011992:Endosomes / Q000821:virology; D006863:Hydrogen-Ion Concentration; D007091:Image Processing, Computer-Assisted; D007668:Kidney; D008051:Lipid Bilayers; D008561:Membrane Fusion / Q000187:drug effects*; D008647:Mesocricetus; D009025:Morpholines / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D012672:Semliki forest virus / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014760:Viral Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure*
D017738:Alkanesulfonic Acids; D008051:Lipid Bilayers; D009025:Morpholines; D014760:Viral Fusion Proteins; C004550:2-(N-morpholino)ethanesulfonic acid