title: The Atomic Structure of the HIV-1 gp41 Transmembrane Domain and Its Connection to the Immunogenic Membrane-proximal External Region.
abstract: The membrane-proximal external region (MPER) C-terminal segment and the transmembrane domain (TMD) of gp41 are involved in HIV-1 envelope glycoprotein-mediated fusion and modulation of immune responses during viral infection. However, the atomic structure of this functional region remains unsolved. Here, based on the high resolution NMR data obtained for peptides spanning the C-terminal segment of MPER and the TMD, we report two main findings: (i) the conformational variability of the TMD helix at a membrane-buried position; and (ii) the existence of an uninterrupted α-helix spanning MPER and the N-terminal region of the TMD. Thus, our structural data provide evidence for the bipartite organization of TMD predicted by previous molecular dynamics simulations and functional studies, but they do not support the breaking of the helix at Lys-683, as was suggested by some models to mark the initiation of the TMD anchor. Antibody binding energetics examined with isothermal titration calorimetry and humoral responses elicited in rabbits by peptide-based vaccines further support the relevance of a continuous MPER-TMD helix for immune recognition. We conclude that the transmembrane anchor of HIV-1 envelope is composed of two distinct subdomains: 1) an immunogenic helix at the N terminus also involved in promoting membrane fusion; and 2) an immunosuppressive helix at the C terminus, which might also contribute to the late stages of the fusion process. The unprecedented high resolution structural data reported here may guide future vaccine and inhibitor developments.
authors: From the Biophysics Unit (Consejo Superior de Investigaciones Científicas, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P. O. Box 644, 48080 Bilbao, Spain.
authors: Beatriz
authors: B
authors: Apellániz
authors: From the Biophysics Unit (Consejo Superior de Investigaciones Científicas, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P. O. Box 644, 48080 Bilbao, Spain, the Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, 113-8656 Tokyo, Japan, and.
authors: Edurne
authors: E
authors: Rujas
authors: the Institute of Physical Chemistry "Rocasolano" (Consejo Superior de Investigaciones Científicas), Serrano 119, E-28006 Madrid, Spain.
authors: Soraya
authors: S
authors: Serrano
authors: the Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, 113-8656 Tokyo, Japan, and.
authors: Koldo
authors: K
authors: Morante
authors: the Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, 113-8656 Tokyo, Japan, and.
authors: Kouhei
authors: K
authors: Tsumoto
authors: the Department of Bioengineering, Graduate School of Engineering, University of Tokyo, Bunkyo-ku, 113-8656 Tokyo, Japan, and jose@bioeng.t.u-tokyo.ac.jp.
authors: Jose M M
authors: JM
authors: Caaveiro
authors: the Institute of Physical Chemistry "Rocasolano" (Consejo Superior de Investigaciones Científicas), Serrano 119, E-28006 Madrid, Spain majimenez@iqfr.csic.es.
authors: M Ángeles
authors: MÁ
authors: Jiménez
authors: From the Biophysics Unit (Consejo Superior de Investigaciones Científicas, UPV/EHU) and Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), P. O. Box 644, 48080 Bilbao, Spain, joseluis.nieva@ehu.es.
authors: José L
authors: JL
authors: Nieva
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015483:HIV Antibodies / Q000276:immunology*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion / Q000276:immunology*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011817:Rabbits; D053586:Virus Internalization
chemical_list: D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments
keywords: AIDS; Human Immunodeficiency Virus (HIV); Immunogenic Domain Structure; Immunosuppressive Domain Structure; MPER Vaccine; Nuclear Magnetic Resonance (NMR); Peptide Conformation; Transmembrane Domain; Vaccine Development