Abstract
Protein-mediated membrane fusion is a highly regulated biological process essential for cellular and organismal functions and infection by enveloped viruses. During viral entry the membrane fusion reaction is catalyzed by specialized protein machinery on the viral surface. These viral fusion proteins undergo a series of dramatic structural changes during membrane fusion where they engage, remodel, and ultimately fuse with the host membrane. The structural and dynamic nature of these conformational changes and their impact on the membranes have long-eluded characterization. Recent advances in structural and biophysical methodologies have enabled researchers to directly observe viral fusion proteins as they carry out their functions during membrane fusion. Here we review the structure and function of type I viral fusion proteins and mechanisms of protein-mediated membrane fusion. We highlight how recent technological advances and new biophysical approaches are providing unprecedented new insight into the membrane fusion reaction.
Highlights
The process of protein-mediated membrane fusion is essential for a range of cellular and organismal functions
Viral fusion proteins are classified into three distinct classes, with the type I fusion proteins being the best characterized to date [1,4,7,8]
The biophysical techniques piloted in studies of HA-mediated membrane fusion may begin to reveal the nature of the conformational changes in these systems, at present much remains to be understood about how the complex set of environmental, receptor-binding, and proteolytic processing triggers are communicated to their fusion subunit machinery
Summary
The process of protein-mediated membrane fusion is essential for a range of cellular and organismal functions. A defining characteristic of type I and II viral fusion proteins is that the pre-fusion conformation is trapped in a high-energy, metastable state with respect to the low-energy, post-fusion conformation [4,7,21]. HA led to the development of the “spring-loaded” mechanistic model for viral membrane fusion that is the prevailing way in which these machines are considered to function [21,22,23,24,25,26,27,28,29,30,31,32] In this model, type I fusion proteins function analogous to taut springs that are poised in a high energy state that, once triggered, rapidly and irreversibly “spring” or refold to the low-energy, post-fusion state. We review our current understanding of the structure and function of type I viral fusion proteins, the structural mechanics of fusion protein activation, and the mechanism of protein-mediated viral membrane fusion
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