Biophysical Society Thematic Meeting - October 13-15, 2015

Biophysics of Proteins at Surfaces: Assembly, Activation, Signaling

Poster Abstracts

7-POS Board 7 Cholesterol-dependent Membrane Fusion Induced by the HIV-1 GP41 MPER-TMD and Blocking by Antibodies Functioning at Membrane Surfaces Pablo Carravilla 1 , Edurne Rujas 1 , Beatriz Apellániz 1 , Aitziber Araujo 1 , Nerea Huarte 1 , Eneko Largo 1 , Soraya Serrano 2 , Carmen Domene 3 , María A. Jiménez 2 , José L. Nieva 1 . 1 Biophysics Unit (CSIC, UPV/EHU) and Dept. of Biochemistry, University of the Basque Country (UPV/EHU, P.O. Box 644, 48080 Bilbao, Spain, 2 Institute of Physical Chemistry “Rocasolano” (CSIC), Serrano 119, E-28006 Madrid, Spain, 3 Chemistry Research Laboratory, Mansfield Road, University of Oxford, Oxford OX1 3TA, United Kingdom. Anti-HIV antibodies 4E10 and 10E8 neutralize practically all viral strains and isolates tested in standard assays. These ‘pan-neutralizing’ antibodies bind to the gp41 membrane proximal external region (MPER)-transmembrane domain (TMD) junction at the membrane surface of virions poised for fusion and block the process. The resulting broad neutralization underscores the conservation and functionality of the MPER-TMD region. In recent work, we have described that peptides representing this region have potent membrane-destabilizing effects. Here, based on the outcome of NMR structural studies, vesicle assays, atomic force microscopy characterization and molecular dynamics simulations, we propose a mechanism for the involvement of the MPER-TMD region in HIV-1 fusion, which is dependent on the high cholesterol content accumulated in the viral envelope. In addition, we provide evidence that underpins the potential use of its activity as a new target for inhibitor and immunogen development.

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