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Enhancing mRNA Interactions by Engineering the Arc Protein with Nucleocapsid Domain

Vaibhav Upadhayay1, Wenchao Gu2, Qiuming Yu1

  • 1Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York 14853, United States.

Langmuir : the ACS Journal of Surfaces and Colloids
|October 21, 2024
PubMed

Insights

Mammalian Arc protein

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Virology

Background:

  • Activity-regulated cytoskeleton-associated protein (Arc) forms virus-like capsids for intracellular mRNA transport.
  • HIV-1 Group-specific Antigen (Gag) binds viral mRNA via its Nucleocapsid (NC) domain.
  • Mammalian Arc lacks an NC domain, leaving its mRNA binding interactions unclear.

Purpose of the Study:

  • To investigate the direct mRNA binding interactions of rat Arc.
  • To explore the role of the HIV-1 NC domain in Arc-mediated mRNA binding.
  • To assess the influence of Arc's N-terminal domain-C-terminal assembly (NTD-CA) on mRNA binding.

Main Methods:

  • In vitro binding assays were performed using rat Arc (rArc) and modified rArc constructs with rat Arc 5' UTR (A5U), HIV-1 5' UTR (H5U), and GFP mRNAs.
  • Binding affinities were quantified and compared between different protein-mRNA combinations.
  • The contribution of the HIV-1 Nucleocapsid (NC) domain and rArc's NTD-CA was evaluated.

Main Results:

  • Native rat Arc exhibited weak, non-specific binding to A5U, H5U, and GFP mRNAs.
  • Fusion of the HIV-1 NC domain to rArc significantly enhanced binding to H5U and A5U.
  • The rArc NTD-CA domain was found to facilitate mRNA binding by the retroviral NC domain.

Conclusions:

  • Mammalian Arc and HIV-1 Gag share conserved mechanisms for protein-mRNA interactions.
  • The NTD-CA domain of Arc plays a crucial role in enhancing mRNA binding.
  • Findings suggest potential for novel mRNA delivery systems by combining Gag NTD-CA with retroviral NC and UTRs.

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