Tài liệu Báo cáo khoa học: The capsid protein of human immunodeficiency virus: intersubunit

MINIREVIEW

The capsid protein of human immunodeficiency

virus: intersubunit interactions during virus assembly

Mauricio G. Mateu

Centro de Biologı´a Molecular ‘Severo Ochoa’ (CSIC-UAM), Universidad Auto´noma de Madrid, Spain

Introduction

During HIV-1 morphogenesis [1,2], the capsid protein

(CA; or p24) participates in two distinct assembly

events. The first occurs inside the cell and involves the

Gag polyprotein, of which CA constitutes a part. A

spherical capsid comprising up to 5000 Gag subunits is

formed through self-association around a dimer of the

viral RNA genome, which is encapsidated along with

several viral and cellular proteins. Assembly-competent

Gag molecules are bound to the plasma membrane

and may directly interact with molecules of the viral

envelope polyprotein, which are embedded in the

membrane. Thus, condensation of the capsid drives its

coating by an envelope polyprotein-containing lipid

bilayer. As a result of this morphogenetic process, an

immature, non-infectious HIV-1 particle buds from the

infected cell.

Keywords

capsid; conformational stability and

dynamics; human immunodeficiency virus;

molecular recognition; protein association;

protein conformation; protein structure–

function relationships; virus assembly

Correspondence

M. G. Mateu, Centro de Biologı´a Molecular

‘Severo Ochoa’, Universidad Auto´noma de

Madrid, Cantoblanco, 28049 Madrid, Spain

Fax: +34 91 1964420

Tel: +34 91 1964575

E-mail: [email protected]

Website: http://www.cbm.uam.es/

mkfactory.esdomain/webs/CBMSO/

plt_LineasInvestigacion.aspx?

IdObjeto=19&ChangeLanguage=2

(Received 23 February 2009, revised 12

August 2009, accepted 20 August 2009)

doi:10.1111/j.1742-4658.2009.07313.x

The capsid protein (CA) of HIV-1 is composed of two domains, the N-ter￾minal domain (NTD) and the C-terminal domain (CTD). During the

assembly of the immature HIV-1 particle, both CA domains constitute a

part of the Gag polyprotein, which forms a spherical capsid comprising up

to 5000 radially arranged, extended subunits. Gag–Gag interactions in the

immature capsid are mediated in large part by interactions between CA

domains, which are involved in the formation of a lattice of connected Gag

hexamers. After Gag proteolysis during virus maturation, the CA protein

is released, and approximately 1000–1500 free CA subunits self-assemble

into a truncated cone-shaped capsid. In the mature capsid, NTD–NTD

and NTD–CTD interfaces are involved in the formation of CA hexamers,

and CTD–CTD interfaces connect neighboring hexamers through homodi￾merization. The CA–CA interfaces involved in the assembly of the imma￾ture capsid and those forming the mature capsid are different, at least in

part. CA appears to have evolved an extraordinary conformational plastic￾ity, which allows the creation of multiple CA–CA interfaces and the occur￾rence of CA conformational switches. This minireview focuses on recent

structure–function studies of the diverse CA–CA interactions and interfaces

involved in HIV-1 assembly. Those studies are leading to a better under￾standing of molecular recognition events during virus morphogenesis, and

are also relevant for the development of anti-HIV drugs that are able to

interfere with capsid assembly or disassembly.

Abbreviations

CA, capsid protein of HIV-1; cryoEM, cryoelectron microscopy; cryoET, cryoelectron tomography; CTD, C-terminal domain of CA; EM,

electron microscopy; H–D, hydrogen–deuterium; MA, matrix protein; MHR, major homology region; MLV, murine leukemia virus; NC,

nucleocapsid protein; NTD, N-terminal domain of CA; RSV, Rous sarcoma virus.

6098 FEBS Journal 276 (2009) 6098–6109 ª 2009 The Author Journal compilation ª 2009 FEBS