Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly

Dominik Herrmann, Heather M Hanson, Lynne W. Zhou, Rayna Addabbo, Nora A Willkomm, Isaac Angert, Joachim D. Mueller, Louis M. Mansky, Jamil S. Saad

Research output: Contribution to journalArticlepeer-review

Abstract

Assembly of human T-cell leukemia virus type 1 (HTLV-1) particles is initiated by the trafficking of virally encoded Gag polyproteins to the inner leaflet of the plasma membrane (PM). Gag–PM interactions are mediated by the matrix (MA) domain, which contains a myristoyl group (myr) and a basic patch formed by lysine and arginine residues. For many retroviruses, Gag–PM interactions are mediated by phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]; however, previous studies suggested that HTLV-1 Gag–PM interactions and therefore virus assembly are less dependent on PI(4,5)P2. We have recently shown that PI(4,5)P2 binds directly to HTLV-1 unmyristoylated MA [myr(–)MA] and that myr(–)MA binding to membranes is significantly enhanced by inclusion of phosphatidylserine (PS) and PI(4,5)P2. Herein, we employed structural, biophysical, biochemical, mutagenesis, and cell-based assays to identify residues involved in MA–membrane interactions. Our data revealed that the lysine-rich motif (Lys47, Lys48, and Lys51) constitutes the primary PI(4,5)P2–binding site. Furthermore, we show that arginine residues 3, 7, 14 and 17 located in the unstructured N-terminus are essential for MA binding to membranes containing PS and/or PI(4,5)P2. Substitution of lysine and arginine residues severely attenuated virus-like particle production, but only the lysine residues could be clearly correlated with reduced PM binding. These results support a mechanism by which HTLV-1 Gag targeting to the PM is mediated by a trio engagement of the myr group, Arg-rich and Lys-rich motifs. These findings advance our understanding of a key step in retroviral particle assembly.

Original languageEnglish (US)
Article number167609
JournalJournal of Molecular Biology
Volume434
Issue number12
DOIs
StatePublished - Jun 30 2022

Bibliographical note

Funding Information:
This work was supported by grants 9 R01 AI150901-10 from the National Institutes of Health (NIH) to JSS; R01 GM098550 (to LMM); T32 AI083196 and F31 AI147805 (to HMH), T90 DE022732 and F30 DE031829 (to NAW), TL1R002493 (to RA); and T90 DE022732 (to IA). The High-Field NMR facility at the University of Alabama at Birmingham was established through NIH grant 1S10RR026478 and is currently supported through the O'Neal Comprehensive Cancer center (NCI grant P30 CA013148). The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding Information:
This work was supported by grants 9 R01 AI150901-10 from the National Institutes of Health (NIH) to JSS; R01 GM098550 (to LMM); T32 AI083196 and F31 AI147805 (to HMH), T90 DE022732 and F30 DE031829 (to NAW), TL1R002493 (to RA); and T90 DE022732 (to IA). The High-Field NMR facility at the University of Alabama at Birmingham was established through NIH grant 1S10RR026478 and is currently supported through the O’Neal Comprehensive Cancer center (NCI grant P30 CA013148).

Publisher Copyright:
© 2022 Elsevier Ltd

Keywords

  • Gag polyprotein
  • human T-cell leukemia virus type 1 (HTLV-1)
  • human immunodeficiency virus type 1 (HIV-1)
  • matrix (MA) protein
  • plasma membrane (PM)

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly'. Together they form a unique fingerprint.

Cite this