Histidine protonation and the activation of viral fusion proteins

2008 ◽  
Vol 36 (1) ◽  
pp. 43-45 ◽  
Author(s):  
Daniela S. Mueller ◽  
Thorsten Kampmann ◽  
Ragothaman Yennamalli ◽  
Paul R. Young ◽  
Bostjan Kobe ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Envelope Protein ◽  
Fusion Proteins ◽  
Side Chain ◽  
Viral Fusion ◽  
Histidine Residues ◽  
Local Environments ◽  
Viral Fusion Proteins ◽  
Dynamics Simulations

Many viral fusion proteins only become activated under mildly acidic condition (pH 4.5–6.5) close to the pKa of histidine side-chain protonation. Analysis of the sequences and structures of influenza HA (haemagglutinin) and flaviviral envelope glycoproteins has led to the identification of a number of histidine residues that are not only fully conserved themselves but have local environments that are also highly conserved [Kampmann, Mueller, Mark, Young and Kobe (2006) Structure 14, 1481–1487]. Here, we summarize studies aimed at determining the role, if any, that protonation of these potential switch histidine residues plays in the low-pH-dependent conformational changes associated with fusion activation of a flaviviral envelope protein. Specifically, we report on MD (Molecular Dynamics) simulations of the DEN2 (dengue virus type 2) envelope protein ectodomain sE (soluble E) performed under varied pH conditions designed to test the histidine switch hypothesis of Kampmann et al. (2006).

scholarly journals New Biophysical Approaches Reveal the Dynamics and Mechanics of Type I Viral Fusion Machinery and Their Interplay with Membranes

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 413 ◽  
Author(s):  
Mark A. Benhaim ◽  
Kelly K. Lee
Keyword(s):  
Membrane Fusion ◽  
Conformational Changes ◽  
Viral Entry ◽  
Fusion Proteins ◽  
Structural Changes ◽  
Fusion Reaction ◽  
Type I ◽  
Viral Fusion ◽  
Technological Advances ◽  
Viral Fusion Proteins

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.

scholarly journals Protonation of Individual Histidine Residues Is Not Required for the pH-Dependent Entry of West Nile Virus: Evaluation of the “Histidine Switch” Hypothesis

2009 ◽  
Vol 83 (23) ◽  
pp. 12631-12635 ◽  
Author(s):  
Steevenson Nelson ◽  
Subhajit Poddar ◽  
Tsai-Yu Lin ◽  
Theodore C. Pierson
Keyword(s):  
Life Cycle ◽  
West Nile Virus ◽  
Fusion Proteins ◽  
Viral Fusion ◽  
Ph Sensing ◽  
West Nile ◽  
Histidine Residues ◽  
E Protein ◽  
Viral Fusion Proteins ◽  
Ph Dependent

ABSTRACT Histidine residues have been hypothesized to function as sensors of environmental pH that can trigger the activity of viral fusion proteins. We investigated a requirement for histidine residues in the envelope (E) protein of West Nile virus during pH-dependent entry into cells. Each histidine was individually replaced with a nonionizable amino acid and tested functionally. In each instance, mutants capable of orchestrating pH-dependent infection were identified. These results do not support a requirement for any single histidine as a pH-sensing “switch,” and they suggest that additional features of the E protein are involved in triggering pH-dependent steps in the flavivirus life cycle.

scholarly journals Role of Electrostatic Repulsion in Controlling pH-Dependent Conformational Changes of Viral Fusion Proteins

Structure ◽  
2013 ◽  
Vol 21 (7) ◽  
pp. 1085-1096 ◽  
Author(s):  
Joseph S. Harrison ◽  
Chelsea D. Higgins ◽  
Matthew J. O’Meara ◽  
Jayne F. Koellhoffer ◽  
Brian A. Kuhlman ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Fusion Proteins ◽  
Electrostatic Repulsion ◽  
Viral Fusion ◽  
Viral Fusion Proteins ◽  
Ph Dependent

scholarly journals Transmembrane Domains of Highly Pathogenic Viral Fusion Proteins Exhibit Trimeric Association In Vitro

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
pp. e00047-18 ◽  
Author(s):  
Stacy R. Webb ◽  
Stacy E. Smith ◽  
Michael G. Fried ◽  
Rebecca Ellis Dutch
Keyword(s):  
Fusion Protein ◽  
Conformational Changes ◽  
Fusion Proteins ◽  
Ebola Virus ◽  
Transmembrane Domain ◽  
Transmembrane Domains ◽  
Viral Fusion ◽  
Viral Fusion Proteins ◽  
The Stability ◽  
The Right

ABSTRACT Enveloped viruses require viral fusion proteins to promote fusion of the viral envelope with a target cell membrane. To drive fusion, these proteins undergo large conformational changes that must occur at the right place and at the right time. Understanding the elements which control the stability of the prefusion state and the initiation of conformational changes is key to understanding the function of these important proteins. The construction of mutations in the fusion protein transmembrane domains (TMDs) or the replacement of these domains with lipid anchors has implicated the TMD in the fusion process. However, the structural and molecular details of the role of the TMD in these fusion events remain unclear. Previously, we demonstrated that isolated paramyxovirus fusion protein TMDs associate in a monomer-trimer equilibrium, using sedimentation equilibrium analytical ultracentrifugation. Using a similar approach, the work presented here indicates that trimeric interactions also occur between the fusion protein TMDs of Ebola virus, influenza virus, severe acute respiratory syndrome coronavirus (SARS CoV), and rabies virus. Our results suggest that TM-TM interactions are important in the fusion protein function of diverse viral families. IMPORTANCE Many important human pathogens are enveloped viruses that utilize membrane-bound glycoproteins to mediate viral entry. Factors that contribute to the stability of these glycoproteins have been identified in the ectodomain of several viral fusion proteins, including residues within the soluble ectodomain. Although it is often thought to simply act as an anchor, the transmembrane domain of viral fusion proteins has been implicated in protein stability and function as well. Here, using a biophysical approach, we demonstrated that the fusion protein transmembrane domains of several deadly pathogens—Ebola virus, influenza virus, SARS CoV, and rabies virus—self-associate. This observation across various viral families suggests that transmembrane domain interactions may be broadly relevant and serve as a new target for therapeutic development.

Structural comparison of three viral “fusion” proteins

1991 ◽  
Vol 19 (3) ◽  
pp. 312S-312S
Author(s):  
BRUCE H NICHOLSON ◽  
MAHMOUD NAASE
Keyword(s):  
Fusion Proteins ◽  
Viral Fusion ◽  
Structural Comparison ◽  
Viral Fusion Proteins

scholarly journals The intercalation of imidazoacridinones into DNA induces conformational changes in their side chain.

2000 ◽  
Vol 47 (1) ◽  
pp. 65-78 ◽  
Author(s):  
J Mazerski ◽  
K Muchewicz
Keyword(s):  
Conformational Changes ◽  
Ring System ◽  
Van Der Waals Interactions ◽  
Side Chain ◽  
Intercalation Complex ◽  
Highly Active ◽  
Antitumor Compounds ◽  
Chemical Constitution ◽  
Modelling Techniques ◽  
Dynamics Simulations

Imidazoacridinones (IAs) are a new group of highly active antitumor compounds. The intercalation of the IA molecule into DNA is the preliminary step in the mode of action of these compounds. There are no experimental data about the structure of an intercalation complex formed by imidazoacridinones. Therefore the design of new potentially better compounds of this group should employ the molecular modelling techniques. The results of molecular dynamics simulations performed for four IA analogues are presented. Each of the compounds was studied in two systems: i) in water, and ii) in the intercalation complex with dodecamer duplex d(GCGCGCGCGCGC)2. Significant differences in the conformation of the side chain in the two environments were observed for all studied IAs. These changes were induced by electrostatic as well as van der Waals interactions between the intercalator and DNA. Moreover, the results showed that the geometry of the intercalation complex depends on: i) the chemical constitution of the side chain, and ii) the substituent in position 8 of the ring system.

Peptide models for the membrane destabilizing actions of viral fusion proteins

Biopolymers ◽  
1992 ◽  
Vol 32 (4) ◽  
pp. 309-314 ◽  
Author(s):  
Richard M. Epand ◽  
James J. Cheetham ◽  
Raquel F. Epand ◽  
Philip L. Yeagle ◽  
Christopher D. Richardson ◽  
...  
Keyword(s):  
Fusion Proteins ◽  
Viral Fusion ◽  
Peptide Models ◽  
Viral Fusion Proteins
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