High-resolution analysis of the human T-cell leukemia virus capsid protein reveals insights into immature particle morphology
Open Access
- 11 December 2025
- journal article
- research article
- Published by Springer Nature in Nature Communications
- Vol. 17 (1)
Abstract
Infection with human T-cell leukemia virus type 1 (HTLV-1) can result in adult T-cell leukemia/lymphoma and HTLV-1 associated-myelopathy/tropical spastic paraparesis. The Gag polyprotein – the major structural protein – is crucial for driving virus particle assembly, with the capsid (CA) domain as the key determinant for Gag multimerization. Here, we characterize the immature CA lattice from immature virus particles by using cryo-electron microscopy and tomography (cryo-EM/ET). We report resolving the immature CA lattice to 3.4 Å resolution by single particle analysis (SPA). Our reconstruction reveals that the lattice is stabilized through a trimeric NTD inter-hexamer interface and a dimeric CTD inter-hexamer interface. Further analysis by cryo-ET reveals clear heterogeneity, notably the varying lattice curvatures and the varying distances from the CA layer to the membrane. Intriguingly, inositol hexakisphosphate (IP6) is dispensable for HTLV-1 immature particle assembly and proper immature lattice formation. These observations provide deeper insights into the molecular basis of HTLV-1 immature particle morphology as well as aid in revealing therapeutic targets.Keywords
Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (R01 GM151775)
- U.S. Department of Health & Human Services | National Institutes of Health (R21 DE032878)
- U.S. Department of Health & Human Services | National Institutes of Health (F31 AI184673)
- U.S. Department of Health & Human Services | National Institutes of Health (T32 AI083196)
- U.S. Department of Health & Human Services | National Institutes of Health (T32DA007097)
- U.S. Department of Health & Human Services | National Institutes of Health (F32AI150351)
- U.S. Department of Health & Human Services | National Institutes of Health (U24 GM116789)
- U.S. Department of Health & Human Services | National Institutes of Health (R01 AI178846)
- U.S. Department of Health & Human Services | National Institutes of Health (U54 AI170791)
- American Cancer Society (PF-21-189-01-MPC)
This publication has 80 references indexed in Scilit:
- HIV-2 Immature Particle Morphology Provides Insights into Gag Lattice Stability and Virus MaturationJournal of Molecular Biology, 2023
- Structural Insights into the Mechanism of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for AssemblyJournal of Molecular Biology, 2021
- Perturbing the energy landscape for improved packing during computational protein designProteins: Structure, Function, and Bioinformatics, 2020
- Cellular IP6 Levels Limit HIV Production while Viruses that Cannot Efficiently Package IP6 Are Attenuated for Infection and ReplicationCell Reports, 2019
- MolProbity: More and better reference data for improved all‐atom structure validationProtein Science, 2017
- Alternate States of Proteins Revealed by Detailed Energy Landscape MappingJournal of Molecular Biology, 2011
- Scalable molecular dynamics with NAMDJournal of Computational Chemistry, 2005
- In Vivo Homodimerisation of HTLV-1 Gag and MA Gives Clues to the Retroviral Capsid and TM Envelope Protein ArrangementJournal of Molecular Biology, 2004
- Structural analysis of the N-terminal domain of the human T-cell leukemia virus capsid proteinJournal of Molecular Biology, 2001
- Computer Visualization of Three-Dimensional Image Data Using IMODJournal of Structural Biology, 1996