title: Critical role of leucine-valine change in distinct low pH requirements for membrane fusion between two related retrovirus envelopes.
abstract: Many viruses use a pH-dependent pathway for fusion with host cell membrane, the mechanism of which is still poorly understood. Here we report that a subtle leucine (Leu)-valine (Val) change at position 501 in the envelope glycoproteins (Envs) of two related retroviruses, jaagsiekte sheep retrovirus (JSRV) and enzootic nasal tumor virus (ENTV), is responsible for their distinct low pH requirements for membrane fusion and infection. The Leu and Val residues are predicted to reside within the C-terminal heptad repeat (HR2) region of JSRV and ENTV Envs, particularly proximal to the hairpin turn of the putative six-helix bundle (6HB). Substitution of the JSRV Leu with a Val blocked the Env-mediated membrane fusion at pH 5.0, whereas replacement of the ENTV Val with a Leu rendered the ENTV Env capable of fusing at pH 5.0. A Leu-Val change has no apparent effect on the stability of native Env, but appears to stabilize an intermediate induced by receptor binding. These results are consistent with the existence of at least two metastable conformations of these viral glycoproteins, the native prefusion conformation and a receptor-induced metastable intermediate. Collectively, this work represents an interesting perhaps unique example whereby a simple Leu-Val change has critical impact on pH-dependent virus fusion and entry.
authors.affiliation: Department of Molecular Microbiology and Immunology, Bond Life Sciences Center, University of Missouri, Columbia, Missouri 65211, USA.
authors.forename: Marceline
authors.initials: M
authors.lastname: Côté
authors.forename: Yi-Min
authors.initials: YM
authors.lastname: Zheng
authors.forename: Kun
authors.initials: K
authors.lastname: Li
authors.forename: Shi-Hua
authors.initials: SH
authors.lastname: Xiang
authors.forename: Lorraine M
authors.initials: LM
authors.lastname: Albritton
authors.forename: Shan-Lu
authors.initials: SL
authors.lastname: Liu
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D015686:Gene Products, env / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D022141:Jaagsiekte sheep retrovirus / Q000235:genetics / Q000378:metabolism*; D008561:Membrane Fusion; D012756:Sheep; D056224:Viral Structures / Q000235:genetics / Q000378:metabolism*; D053586:Virus Internalization
chemical_list: D015686:Gene Products, env