Structural Transition and Antibody Binding of EBOV GP and ZIKV E Proteins from Pre-Fusion to Fusion-Initiation State.

Anna Lappala,Jacob Miner,Ming Zhang,Benjamin Mcmahon,Paul Fenimore,Wataru Nishima,Will Fischer,Peter Hraber,Chang-Shung Tung

doi:10.3390/biom8020025

Abstract

Membrane fusion proteins are responsible for viral entry into host cells—a crucial first step in viral infection. These proteins undergo large conformational changes from pre-fusion to fusion-initiation structures, and, despite differences in viral genomes and disease etiology, many fusion proteins are arranged as trimers. Structural information for both pre-fusion and fusion-initiation states is critical for understanding virus neutralization by the host immune system. In the case of Ebola virus glycoprotein (EBOV GP) and Zika virus envelope protein (ZIKV E), pre-fusion state structures have been identified experimentally, but only partial structures of fusion-initiation states have been described. While the fusion-initiation structure is in an energetically unfavorable state that is difficult to solve experimentally, the existing structural information combined with computational approaches enabled the modeling of fusion-initiation state structures of both proteins. These structural models provide an improved understanding of four different neutralizing antibodies in the prevention of viral host entry.

Highlights

Enveloped viruses employ a common mechanism to enter the host cell [1]
For the yellow helices to stack on top of the magenta helices as indicated (Protein Data Bank (PDB) accession code 2EBO), they must rearrange from the outside to the inside of the GP1 trimer
To account for the large conformational changes during the pre-fusion-to-fusion transition, a spring-loaded model is applied [37,38]. This same model was considered as the mechanism for the Ebola virus glycoprotein (EBOV GP) structural transition in a previous study by White et al [39] and is supported by structural information of EBOV

Summary

Introduction

Enveloped viruses employ a common mechanism to enter the host cell [1]. The first steps, receptor binding and membrane fusion, are initiated by the envelope protein [2,3,4]. While specific details vary among different viruses, the envelope proteins invariably go through a large conformational change [5,6]. These large conformational changes allow the envelope protein to assume an extended fusion-initiation conformation: the envelope protein in the fusion-initiation state is able to bridge across the viral and the host membranes, subsequently bringing the two membranes into close proximity and starting the fusion process [7,8]. Viral neutralization by antibodies may involve binding to the fusion-state structure or inhibiting its formation.

Methods

Results

Discussion

Conclusion