Structural basis of CD4 downregulation by HIV-1 Nef.

Adaptor Protein Complex 2 / chemistry CD4 Antigens / chemistry Crystallography, X-Ray HIV Infections / metabolism HIV-1 / physiology HeLa Cells Host-Pathogen Interactions Humans Models, Molecular Protein Binding Protein Conformation Protein Domains nef Gene Products, Human Immunodeficiency Virus / chemistry

Journal

Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374

Informations de publication

Date de publication:
09 2020
Historique:
received: 21 01 2020
accepted: 16 06 2020
pubmed: 29 7 2020
medline: 12 11 2020
entrez: 29 7 2020
Statut: ppublish

Résumé

The HIV-1 Nef protein suppresses multiple immune surveillance mechanisms to promote viral pathogenesis and is an attractive target for the development of novel therapeutics. A key function of Nef is to remove the CD4 receptor from the cell surface by hijacking clathrin- and adaptor protein complex 2 (AP2)-dependent endocytosis. However, exactly how Nef does this has been elusive. Here, we describe the underlying mechanism as revealed by a 3.0-Å crystal structure of a fusion protein comprising Nef and the cytoplasmic domain of CD4 bound to the tetrameric AP2 complex. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. A pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two of Nef's activities and sensitize the virus to immune clearance.

Identifiants

DOI: 10.1038/s41594-020-0463-z PMID: 32719457 PMC: PMC7483821
pubmed: 32719457
doi: 10.1038/s41594-020-0463-z
pii: 10.1038/s41594-020-0463-z
pmc: PMC7483821
mid: NIHMS1604875
doi:

Substances chimiques

Adaptor Protein Complex 2 0
CD4 Antigens 0
nef Gene Products, Human Immunodeficiency Virus 0
nef protein, Human immunodeficiency virus 1 0

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

822-828

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM083960
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI135990
Pays : United States
Organisme : NIAID NIH HHS
ID : F32 AI127291
Pays : United States
Organisme : NIAID NIH HHS
ID : P50 AI150476
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI129706
Pays : United States
Organisme : NIGMS NIH HHS
ID : P50 GM082250
Pays : United States
Organisme : NIAID NIH HHS
ID : P30 AI036214
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI102778
Pays : United States
Organisme : NIGMS NIH HHS
ID : P41 GM109824
Pays : United States
Organisme : NIH HHS
ID : S10 OD021596
Pays : United States

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Auteurs

Yonghwa Kwon (Y)

Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA, USA.

Robyn M Kaake (RM)

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Gladstone Institutes, San Francisco, CA, USA.

Ignacia Echeverria (I)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.

Marissa Suarez (M)

The VA San Diego Healthcare System, San Diego, CA, USA.

Mohammad Karimian Shamsabadi (M)

Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA, USA.
ORCID: 0000-0003-3392-9951

Charlotte Stoneham (C)

The VA San Diego Healthcare System, San Diego, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Peter W Ramirez (PW)

Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Jacob Kress (J)

Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA, USA.

Rajendra Singh (R)

The VA San Diego Healthcare System, San Diego, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Andrej Sali (A)

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Department of Pharmaceutical Chemistry and Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA, USA.

Nevan Krogan (N)

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Gladstone Institutes, San Francisco, CA, USA.
ORCID: 0000-0003-4902-337X

John Guatelli (J)

The VA San Diego Healthcare System, San Diego, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.

Xiaofei Jia (X)

Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA, USA. xjia@umassd.edu.
ORCID: 0000-0002-0972-3884

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Protéines du transport vésiculaire › Protéines adaptatrices du transport vésiculaire › Complexe protéique adaptateur 2 › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Antigènes de différenciation › Antigènes de différenciation des lymphocytes T › Antigènes CD4 › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Techniques d'investigation › Techniques de chimie analytique › Cristallographie aux rayons X › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Maladies du système immunitaire › Déficits immunitaires › Infections à VIH › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Virus › Virus à ARN › Retroviridae › Lentivirus › Lentivirus des primates › VIH (Virus de l'Immunodéficience Humaine) › VIH-1 (Virus de l'Immunodéficience Humaine de type 1) › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HeLa › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Phénomènes biologiques › Interactions hôte-microbes › Interactions hôte-pathogène › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Métabolisme › Liaison aux protéines › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure tertiaire des protéines › Domaines protéiques › Structural basis of CD4 downregulation by HIV-1 Nef.
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales régulatrices ou accessoires › Produits du gène nef › Produits du gène nef du virus de l'immunodéficience humaine › Structural basis of CD4 downregulation by HIV-1 Nef.