Ectodomain Pulling Combines with Fusion Peptide Inserting to Provide Cooperative Fusion for Influenza Virus and HIV

Sergey A Akimov,Oleg V Batishchev,Oleg V Kondrashov,Joshua Zimmerberg

doi:10.3390/ijms21155411

Abstract

Enveloped viruses include the most dangerous human and animal pathogens, in particular coronavirus, influenza virus, and human immunodeficiency virus (HIV). For these viruses, receptor binding and entry are accomplished by a single viral envelope protein (termed the fusion protein), the structural changes of which trigger the remodeling and merger of the viral and target cellular membranes. The number of fusion proteins required for fusion activity is still under debate, and several studies report this value to range from 1 to 9 for type I fusion proteins. Here, we consider the earliest stage of viral fusion based on the continuum theory of membrane elasticity. We demonstrate that membrane deformations induced by the oblique insertion of amphipathic fusion peptides mediate the lateral interaction of these peptides and drive them to form into a symmetric fusion rosette. The pulling force produced by the structural rearrangements of the fusion protein ectodomains gives additional torque, which deforms the membrane and additionally stabilizes the symmetric fusion rosette, thus allowing a reduction in the number of fusion peptides needed for fusion. These findings can resolve the large range of published cooperativity indices for HIV, influenza, and other type I fusion proteins.

Highlights

Enveloped viruses, as a class, include top human killers such as influenza viruses, human immunodeficiency virus (HIV), coronaviruses, Ebola, and hepatitis C viruses [1]
We considered the interactions of laterally immobile obliquely oriented fusion peptides of type I fusion proteins exemplified by HIV and influenza A virus fusion proteins, which are mediated by the elastic deformations of the membrane
It is thought that the altered spontaneous curvature in the ring-like zone of the fusion rosette might be responsible for the formation of the bulge on the target membrane; the fusing membranes come into close contact at the top of the bulge, which substantially facilitates the merger of membranes

Summary

Introduction

As a class, include top human killers such as influenza viruses, human immunodeficiency virus (HIV), coronaviruses, Ebola, and hepatitis C viruses [1]. As a result of membrane fusion, the viral interior and the cell cytoplasm unite, forming a continuous pathway for viral genetic material [3]. Unlike the fusion of cells, organelles, vesicles, etc., which usually requires large protein complexes and the consumption of energy [4,5], viral fusion is generally orchestrated by fusion proteins without ATP or GTP hydrolysis [3]. These proteins usually represent the oligomeric structures of several monomers, undergoing conformational rearrangements to bring viral and cellular membranes into close contact [3]

Methods

Results

Discussion

Conclusion