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.
MeSH: Amino Acid Sequence, Animals, Chlorocebus aethiops, Distemper Virus, Canine, chemistry, physiology, Endoplasmic Reticulum, metabolism, Measles virus, chemistry, physiology, Membrane Fusion, Molecular Sequence Data, Peptide Fragments, analysis, Protein Conformation, Structure-Activity Relationship, Transfection, Vero Cells, Viral Fusion Proteins, analysis, chemistry, physiology