FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking

Pei Tzu Huang, Brady James Summers, Chaoyi Xu, Juan R. Perilla, Viacheslav Malikov, Mojgan Naghavi, Yong Xiong*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell. In this paper, Huang et al. find that the viral cofactor FEZ1, a kinesin adaptor protein, uses multiple negatively charged amino-acid stretches to avidly interact with the positive center pores of the HIV-1 capsid protein hexamers, associating the virus particles to kinesin motors and thus promoting viral trafficking and infection.

Original languageEnglish (US)
Pages (from-to)2373-2385.e7
JournalCell reports
Volume28
Issue number9
DOIs
StatePublished - Aug 27 2019

Fingerprint

Kinesin
Capsid
HIV-1
Capsid Proteins
Phytic Acid
Viruses
Molecular dynamics
Glutamic Acid
Proteins
Nucleotides
Amino Acids
Atoms
Sensors
Computer simulation
Virus Diseases
Molecular Dynamics Simulation
Microtubules
Virion
Mutation
Infection

Keywords

  • CA
  • FEZ1
  • HIV
  • capsid
  • kinesin adaptor protein
  • microtubule trafficking
  • pattern sensing
  • virus

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Huang, P. T., Summers, B. J., Xu, C., Perilla, J. R., Malikov, V., Naghavi, M., & Xiong, Y. (2019). FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking. Cell reports, 28(9), 2373-2385.e7. https://doi.org/10.1016/j.celrep.2019.07.079
Huang, Pei Tzu ; Summers, Brady James ; Xu, Chaoyi ; Perilla, Juan R. ; Malikov, Viacheslav ; Naghavi, Mojgan ; Xiong, Yong. / FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking. In: Cell reports. 2019 ; Vol. 28, No. 9. pp. 2373-2385.e7.
@article{693b97df415a4016b663a411ce2a1823,
title = "FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking",
abstract = "HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell. In this paper, Huang et al. find that the viral cofactor FEZ1, a kinesin adaptor protein, uses multiple negatively charged amino-acid stretches to avidly interact with the positive center pores of the HIV-1 capsid protein hexamers, associating the virus particles to kinesin motors and thus promoting viral trafficking and infection.",
keywords = "CA, FEZ1, HIV, capsid, kinesin adaptor protein, microtubule trafficking, pattern sensing, virus",
author = "Huang, {Pei Tzu} and Summers, {Brady James} and Chaoyi Xu and Perilla, {Juan R.} and Viacheslav Malikov and Mojgan Naghavi and Yong Xiong",
year = "2019",
month = "8",
day = "27",
doi = "10.1016/j.celrep.2019.07.079",
language = "English (US)",
volume = "28",
pages = "2373--2385.e7",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "9",

}

Huang, PT, Summers, BJ, Xu, C, Perilla, JR, Malikov, V, Naghavi, M & Xiong, Y 2019, 'FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking', Cell reports, vol. 28, no. 9, pp. 2373-2385.e7. https://doi.org/10.1016/j.celrep.2019.07.079

FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking. / Huang, Pei Tzu; Summers, Brady James; Xu, Chaoyi; Perilla, Juan R.; Malikov, Viacheslav; Naghavi, Mojgan; Xiong, Yong.

In: Cell reports, Vol. 28, No. 9, 27.08.2019, p. 2373-2385.e7.

Research output: Contribution to journalArticle

TY - JOUR

T1 - FEZ1 Is Recruited to a Conserved Cofactor Site on Capsid to Promote HIV-1 Trafficking

AU - Huang, Pei Tzu

AU - Summers, Brady James

AU - Xu, Chaoyi

AU - Perilla, Juan R.

AU - Malikov, Viacheslav

AU - Naghavi, Mojgan

AU - Xiong, Yong

PY - 2019/8/27

Y1 - 2019/8/27

N2 - HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell. In this paper, Huang et al. find that the viral cofactor FEZ1, a kinesin adaptor protein, uses multiple negatively charged amino-acid stretches to avidly interact with the positive center pores of the HIV-1 capsid protein hexamers, associating the virus particles to kinesin motors and thus promoting viral trafficking and infection.

AB - HIV-1 uses the microtubule network to traffic the viral capsid core toward the nucleus. Viral nuclear trafficking and infectivity require the kinesin-1 adaptor protein FEZ1. Here, we demonstrate that FEZ1 directly interacts with the HIV-1 capsid and specifically binds capsid protein (CA) hexamers. FEZ1 contains multiple acidic, poly-glutamate stretches that interact with the positively charged central pore of CA hexamers. The FEZ1-capsid interaction directly competes with nucleotides and inositol hexaphosphate (IP6) that bind at the same location. In addition, all-atom molecular dynamic (MD) simulations establish the molecular details of FEZ1-capsid interactions. Functionally, mutation of the FEZ1 capsid-interacting residues significantly reduces trafficking of HIV-1 particles toward the nucleus and early infection. These findings support a model in which the central capsid hexamer pore is a general HIV-1 cofactor-binding hub and FEZ1 serves as a unique CA hexamer pattern sensor to recognize this site and promote capsid trafficking in the cell. In this paper, Huang et al. find that the viral cofactor FEZ1, a kinesin adaptor protein, uses multiple negatively charged amino-acid stretches to avidly interact with the positive center pores of the HIV-1 capsid protein hexamers, associating the virus particles to kinesin motors and thus promoting viral trafficking and infection.

KW - CA

KW - FEZ1

KW - HIV

KW - capsid

KW - kinesin adaptor protein

KW - microtubule trafficking

KW - pattern sensing

KW - virus

UR - http://www.scopus.com/inward/record.url?scp=85070342798&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070342798&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2019.07.079

DO - 10.1016/j.celrep.2019.07.079

M3 - Article

VL - 28

SP - 2373-2385.e7

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 9

ER -