Base of the Measles Virus Fusion Trimer Head Receives the Signal That Triggers Membrane Fusion

Abstract

Background: A homology model of the trimeric measles virus fusion protein predicts a cavity in the base of the head. Results: Hydrophobic residues required for interactions with the hemagglutinin map to this cavity. Conclusion:The base of the measles virus fusion protein trimer head receives the signal that triggers membrane fusion. Significance: Emerging, re-emerging, and prevalent paramyxoviruses may operate based on similar signal transmission mechanisms.The measles virus (MV) fusion (F) protein trimer executes membrane fusion after receiving a signal elicited by receptor binding to the hemagglutinin (H) tetramer. Where and how this signal is received is understood neither for MV nor for other paramyxoviruses. Because only the prefusion structure of the parainfluenza virus 5 (PIV5) F-trimer is available, to study signal receipt by the MV F-trimer, we generated and energy-refined a homology model. We used two approaches to predict surface residues of the model interacting with other proteins. Both approaches measured interface propensity values for patches of residues. The second approach identified, in addition, individual residues based on the conservation of physical chemical properties among F-proteins. Altogether, about 50 candidate interactive residues were identified. Through iterative cycles of mutagenesis and functional analysis, we characterized six residues that are required specifically for signal transmission; their mutation interferes with fusion, although still allowing efficient F-protein processing and cell surface transport. One residue is located adjacent to the fusion peptide, four line a cavity in the base of the F-trimer head, while the sixth residue is located near this cavity. Hydrophobic interactions in the cavity sustain the fusion process and contacts with H. The cavity is flanked by two different subunits of the F-trimer. Tetrameric H-stalks may be lodged in apposed cavities of two F-trimers. Because these insights are based on a PIV5 homology model, the signal receipt mechanism may be conserved among paramyxoviruses.Measles virus (MV), 2 an enveloped nonsegmented negative strand RNA virus, remains a significant public health problem (1). Although targeted for eradication (2), MV still caused 139,000 worldwide deaths in 2010 (3). In addition, relaxed vaccination discipline favored recent measles re-emergence in Europe and North America, now reporting small but costly epidemics (4, 5).MV is a member of the family Paramyxoviridae that includes other deadly emerging viruses such as Hendra and Nipah and prevalent human pathogens such as mumps, parainfluenza, and respiratory syncytial viruses that still cause significant morbidity and mortality (6). Although many other enveloped viruses take advantage of low pH (7) or proteases (8) in the endosomal compartment to trigger membrane fusion, most paramyxoviruses including MV fuse directly with the plasma membrane (6, 9).An accurate mechanism must be in place to secure timely and efficient MV cell entry at the plasma membrane. It is known tha...

Molecular Determinants Defining the Triggering Range of Prefusion F Complexes of Canine Distemper Virus

“…This model is substantiated by the finding that truncated, stabilized MeV H stalks lacking the head domains are sufficient to specifically trigger MeV F (31). Several residues and/or microdomains in the F head domains are suggested to participate in H binding (29,(32)(33)(34)(35).…”

Full Conversion of the Hemagglutinin-Neuraminidase Specificity of the Parainfluenza Virus 5 Fusion Protein by Replacement of 21 Amino Acids in Its Head Region with Those of the Simian Virus 41 Fusion Protein

“…On the basis of the interface propensity and the conservation of physical chemical properties among F proteins, it has been proved that six residues at the base of the MV F head region receive the signal from the MV H protein (31), suggesting that these residues are involved in the H-F interaction. It is worth noting, in this context, that two (Q322 and E325) of the identified six residues correspond to T312 and L315 in PIV5 F segment R, respectively (Fig.…”

LaSota fusion (F) cleavage motif-mediated fusion activity is affected by other regions of the F protein from different genotype Newcastle disease virus in a chimeric virus: implication for virulence attenuation

“…In contrast, in the region 391-420, a single mutation of N403D resulted in a loss of fusion activity and binding reactivity with conformational specific antibody, suggesting that aspartate (the assignment found in AKO and Ban 010) plays a major role in downregulating fusion activity by altering the conformation of the F protein. Recent studies also suggested that this domain may be critical in F and HN interactions or F and H interactions for measles, PIV5 and SV41 (Apte-Sengupta et al, 2012;Bose et al, 2013). It will be of interest in future studies to evaluate whether the N403D mutation affects any of the specific stages of NDV fusion activity and the interaction between the F and HN proteins.…”