Critical role of the human T-Cell leukemia virus type 1 capsid N-Terminal domain for gag-gag interactions and virus particle assembly

Jessica L. Martin, Luiza M. Mendonça, Rachel Marusinec, Jennifer Zuczek, Isaac Angert, Ruth J. Blower, Joachim Mueller, Juan R. Perill, Wei Zhang, Louis M Mansky

Research output: Contribution to journalArticle

Abstract

The retroviral Gag protein is the main structural protein responsible for virus particle assembly and release. Like human immunodeficiency virus type 1 (HIV-1) Gag, human T-cell leukemia virus type 1 (HTLV-1) has a structurally conserved capsid (CA) domain, including a β-hairpin turn and a centralized coiled-coil-like structure of six α helices in the CA amino-terminal domain (NTD), as well as four α-helices in the CA carboxy-terminal domain (CTD). CA drives Gag oligomerization, which is critical for both immature Gag lattice formation and particle production. The HIV-1 CA CTD has previously been shown to be a primary determinant for CA-CA interactions, and while both the HTLV-1 CA NTD and CTD have been implicated in Gag-Gag interactions, our recent observations have implicated the HTLV-1 CA NTD as encoding key determinants that dictate particle morphology. Here, we have conducted alanine-scanning mutagenesis in the HTLV-1 CA NTD nucleotide-encoding sequences spanning the loop regions and amino acids at the beginning and ends of α-helices due to their structural dissimilarity from the HIV-1 CA NTD structure. We analyzed both Gag subcellular distribution and efficiency of particle production for these mutants. We discovered several important residues (i.e., M17, Q47/F48, and Y61). Modeling implicated that these residues reside at the dimer interface (i.e., M17 and Y61) or at the trimer interface (i.e., Q47/F48). Taken together, these observations highlight the critical role of the HTLV-1 CA NTD in Gag-Gag interactions and particle assembly, which is, to the best of our knowledge, in contrast to HIV-1 and other retroviruses.

Original languageEnglish (US)
Article numbere00333-18
JournalJournal of virology
Volume92
Issue number14
DOIs
StatePublished - Jul 1 2018

Fingerprint

Deltaretrovirus
Virus Assembly
capsid
Capsid
virion
Virion
Human immunodeficiency virus 1
HIV-1
Retroviridae
Virus Release
gag Gene Products
structural proteins
mutagenesis

Keywords

  • Deltaretrovirus
  • Gag
  • Lentiviruses
  • Morphology
  • Oligomerization
  • Retrovirus
  • Virus assembly

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

Critical role of the human T-Cell leukemia virus type 1 capsid N-Terminal domain for gag-gag interactions and virus particle assembly. / Martin, Jessica L.; Mendonça, Luiza M.; Marusinec, Rachel; Zuczek, Jennifer; Angert, Isaac; Blower, Ruth J.; Mueller, Joachim; Perill, Juan R.; Zhang, Wei; Mansky, Louis M.

In: Journal of virology, Vol. 92, No. 14, e00333-18, 01.07.2018.

Research output: Contribution to journalArticle

Martin, Jessica L. ; Mendonça, Luiza M. ; Marusinec, Rachel ; Zuczek, Jennifer ; Angert, Isaac ; Blower, Ruth J. ; Mueller, Joachim ; Perill, Juan R. ; Zhang, Wei ; Mansky, Louis M. / Critical role of the human T-Cell leukemia virus type 1 capsid N-Terminal domain for gag-gag interactions and virus particle assembly. In: Journal of virology. 2018 ; Vol. 92, No. 14.
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AU - Marusinec, Rachel

AU - Zuczek, Jennifer

AU - Angert, Isaac

AU - Blower, Ruth J.

AU - Mueller, Joachim

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AB - The retroviral Gag protein is the main structural protein responsible for virus particle assembly and release. Like human immunodeficiency virus type 1 (HIV-1) Gag, human T-cell leukemia virus type 1 (HTLV-1) has a structurally conserved capsid (CA) domain, including a β-hairpin turn and a centralized coiled-coil-like structure of six α helices in the CA amino-terminal domain (NTD), as well as four α-helices in the CA carboxy-terminal domain (CTD). CA drives Gag oligomerization, which is critical for both immature Gag lattice formation and particle production. The HIV-1 CA CTD has previously been shown to be a primary determinant for CA-CA interactions, and while both the HTLV-1 CA NTD and CTD have been implicated in Gag-Gag interactions, our recent observations have implicated the HTLV-1 CA NTD as encoding key determinants that dictate particle morphology. Here, we have conducted alanine-scanning mutagenesis in the HTLV-1 CA NTD nucleotide-encoding sequences spanning the loop regions and amino acids at the beginning and ends of α-helices due to their structural dissimilarity from the HIV-1 CA NTD structure. We analyzed both Gag subcellular distribution and efficiency of particle production for these mutants. We discovered several important residues (i.e., M17, Q47/F48, and Y61). Modeling implicated that these residues reside at the dimer interface (i.e., M17 and Y61) or at the trimer interface (i.e., Q47/F48). Taken together, these observations highlight the critical role of the HTLV-1 CA NTD in Gag-Gag interactions and particle assembly, which is, to the best of our knowledge, in contrast to HIV-1 and other retroviruses.

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KW - Retrovirus

KW - Virus assembly

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