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Principal Investigator: Maolin Lu
Organization: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
Fiscal Year: 2024
Award: $372,500
Funding agency: National Institute of General Medical Sciences
Research Abstract: The spike/fusion glycoproteins residing on the surface of human enveloped viruses are
targets of immune response and are the focus of researchers developing vaccines and antiviral treatments. The
conformational dynamics of spike proteins drive the entry of enveloped viruses into cells via viral membrane
fusion and facilitate antibody recognition. However, the lack of deep insights into dynamics has prevented a
complete elucidation of the molecular mechanism by which spike proteins promote virus entry. Many viruses,
such as coronavirus SARS-CoV-2, respiratory syncytial virus (RSV), and HIV-1, share a similar viral fusion
mechanism (type-I) mediated by their respective spike proteins. These spikes undergo dramatic structural
changes, and the energy released from conformational transitions overcomes the fusion kinetic barriers.
However, our understanding of the multi-step fusion process mainly relies on individual structural snapshots of
spike proteins at fusion endpoints. How these endpoints are correlated in a time-resolved manner and the order
and frequency of conformational events underlying virus entry remain largely elusive. The proposed research
extends our efforts to explore viral membrane fusion and is supported by our experience probing the
conformational dynamics of the SARS-CoV-2 spike (S) and HIV-1 envelope (Env) glycoproteins. The overarching
goal of this project is to integrate our knowledge into a generic working model that will describe a time-resolved
stepwise framework of the type-I fusion mechanism, in which the conformational trajectories of fusion proteins
are explicitly defined in space and time. We pioneered the use of the single-molecule Förster resonance energy
transfer (smFRET) to study S and revealed multiple S conformations on the virus. We delineated sequential
transitions of S from closed to open conformations upon activation by cellular receptors. We provided the first
experimental evidence of decelerated transition dynamics from open states, suggesting increased stability of the
fusion-reactive open state to be part of the SARS-CoV-2 adaption strategies. Here, we will use an integrated
platform of smFRET and virus-to-cell fusion in combination with computational and structural tools to reveal the
conformational plasticity S adapts during virus evolution and to visualize the conformational trajectory S
undergoes during fusion. We will perform comparative studies on another respiratory virus - RSV fusion (F)
protein, with interest in other type-I spike proteins of newly emerging viruses. We will elucidate conformational
events and transition dynamics of F-mediated viral membrane fusion and evaluate whether conformation-
presentation of F-based vaccine candidates represents the predominant state exposed to the host. The studies
are expected to allow us to identify the common and divergent traits of the S- and F-mediated fusion processes
that will advance our knowledge and help us define the common theme of the type-I fusion mechanism. We
envision that this program of research using different advanced technologies will reveal unrecognized insights
into virus entry that lay the foundation for advances in anti-viral interventions, in line with the mission of NIGMS.
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