Canine distemper virus and measles virus fusion glycoprotein trimers: partial membrane-proximal ectodomain cleavage enhances function.
The trimeric fusion (F) glycoproteins of morbilliviruses are activated by furin cleavage of the precursor F(0) into the F(1) and F(2) subunits. Here we show that an additional membrane-proximal cleavage occurs and modulates F protein function. We initially observed that the ectodomain of approximately one in three measles virus (MV) F proteins is cleaved proximal to the membrane. Processing occurs after cleavage activation of the precursor F(0) into the F(1) and F(2) subunits, producing F(1a) and F(1b) fragments that are incorporated in viral particles. We also detected the F(1b) fragment, including the transmembrane domain and cytoplasmic tail, in cells expressing the canine distemper virus (CDV) or mumps virus F protein. Six membrane-proximal amino acids are necessary for efficient CDV F(1a/b) cleavage. These six amino acids can be exchanged with the corresponding MV F protein residues of different sequence without compromising function. Thus, structural elements of different sequence are functionally exchangeable. Finally, we showed that the alteration of a block of membrane-proximal amino acids results in diminished fusion activity in the context of a recombinant CDV. We envisage that selective loss of the membrane anchor in the external subunits of circularly arranged F protein trimers may disengage them from pulling the membrane centrifugally, thereby facilitating fusion pore formation.
von Messling
Veronika
V
Molecular Medicine Program, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA.
Milosevic
Dragana
D
Devaux
Patricia
P
Cattaneo
Roberto
R
D000595:Amino Acid Sequence; D000818:Animals; D002522:Chlorocebus aethiops; D004217:Distemper Virus, Canine / Q000737:chemistry* / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008459:Measles virus / Q000737:chemistry* / Q000502:physiology; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000032:analysis; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014162:Transfection; D014709:Vero Cells; D014760:Viral Fusion Proteins / Q000032:analysis / Q000737:chemistry* / Q000502:physiology
D010446:Peptide Fragments; D014760:Viral Fusion Proteins