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 D. 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

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 D.; 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 D. ; 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 D.

AU - Perill, Juan R.

AU - Zhang, Wei

AU - Mansky, Louis M.

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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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