Atomic-level modelling of the HIV capsid

Abstract

The mature capsids of human immunodeficiency virus type 1 (HIV-1) and other retroviruses are fullerene shells, composed of the viral CA protein, that enclose the viral genome and facilitate its delivery into new host cells1. Retroviral CA proteins contain independently-folded N-terminal and C-terminal domains (NTD and CTD) that are connected by a flexible linker2–4. The NTD forms either hexameric or pentameric rings, whereas the CTD forms symmetric homodimers that connect the rings into a hexagonal lattice3,5–13. We previously used a disulfide crosslinking strategy to enable isolation and crystallization of soluble HIV-1 CA hexamers11,14. By the same approach, we have now determined the X-ray structure of the HIV-1 CA pentamer at 2.5 Å resolution. Two mutant CA proteins with engineered disulfides at different positions (P17C/T19C and N21C/A22C) converged onto the same quaternary structure, indicating that the disulfide-crosslinked proteins recapitulate the structure of the native pentamer. Assembly of the quasi-equivalent hexamers and pentamers requires remarkably subtle rearrangements in subunit interactions, and appears to be controlled by an electrostatic switch that favors hexamers over pentamers. This study completes the gallery of sub-structures describing the components of the HIV-1 capsid and enables atomic level modeling of the complete capsid. Rigid-body rotations around two assembly interfaces appear sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone.

Cryo-electron microscopy of tubular arrays of HIV-1 Gag resolves structures essential for immature virus assembly

“…Recently, a series of breakthrough studies have revolutionized our understanding of how the CA domains self-assemble to form the mature capsid core of the virus (6)(7)(8), and a pseudoatomic model for the assembled mature core is now available (9). In contrast, much less structural information is available on the immature virus.…”

Monte Carlo Simulations of HIV Capsid Protein Homodimer

“…The self-assembly of the CA proteins has been extensively studied using X-ray, NMR, and cryo-electron microscopy (Cryo-EM). [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Remarkably, a complete atomic model of the capsid was recently obtained by Cryo-EM combined with all-atom simulations. 17 Other theoretical and computational studies [27][28][29][30] also provided important insight into the structure and the assembling process for the HIV capsid.…”

Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

“…The Gag protein forms a hexameric lattice, driven primarily by CA-CA interactions. Whereas the structure of CA in mature particles has been studied extensively, with many high-resolution structures now available (13)(14)(15)(16), and recently progress has been made in determining the structure of the immature Gag lattice (17), the organization of MA in particles has proven difficult to address directly, with no long-range order discernable for the MA shell. The structure of HIV-1 MA has been solved in vitro, using both NMR and crystallography approaches (18,19).…”