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Genetically flexible but conserved: a new essential motif in the C-ter domain of HIV-1 group M integrases
bioRxiv - Molecular Biology Pub Date : 2020-05-31 , DOI: 10.1101/2020.05.26.118158
Marine Kanja; Pierre Cappy; Nicolas Levy; Oyndamola Oladosu; Sylvie Schmidt; Paola Rossolillo; Flore Winter; Romain Gasser; Christiane Moog; Marc Ruff; Matteo Negroni; Daniela Lener

Using coevolution-network interference based on the comparison of two phylogenetically distantly related isolates, one from the main group M and the other from the minor group O of HIV-1, we identify, in the C-terminal domain (CTD) of integrase, a new functional motif constituted by four non-contiguous amino acids (N222K240N254K273). Mutating the lysines abolishes integration through decreased 3'-processing and inefficient nuclear import of reverse transcribed genomes. Solution of the crystal structures of wt and mutated CTDs shows that the motif generates a positive surface potential that is important for integration. The number of charges in the motif appears more crucial than their position within the motif. Indeed, the positions of the K could be permutated or additional K could be inserted in the motif, generally without affecting integration per se. Despite this potential genetic flexibility, the NKNK arrangement is strictly conserved in natural sequences, indicative of an effective purifying selection exerted at steps other than integration. Accordingly, reverse transcription was reduced even in the mutants that retained wt integration levels, indicating that specifically the wt sequence is optimal for carrying out the multiple functions integrase exerts. We propose that the existence of several amino acids arrangements within the motif, with comparable efficiencies of integration per se, might have constituted an asset for the acquisition of additional functions during viral evolution.
更新日期:2020-05-31

 

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