title: Mechanism of Structural Tuning of the Hepatitis C Virus Human Cellular Receptor CD81 Large Extracellular Loop.
abstract: Hepatitis C virus (HCV) enters into human hepatocytes via tetraspanin hCD81. HCV glycoprotein E2 recognizes the "head" subdomain of the large extracellular loop (LEL) of CD81 (hCD81LEL), but the precise mechanism of virus cell attachment and entry remains elusive. Here, by combining the structural analysis of a conspicuous number of crystallized CD81LELmolecules with molecular dynamics simulations, we show that the conformational plasticity of the hCD81LELhead subdomain is a molecular property of the receptor. The observed closed, intermediate, and open conformations of the head subdomain provide distinct binding platforms. Simulations at pH 7.4 and 4.0 indicate that this dynamism is pH modulated. The crystallized double conformation of the disulfide bridge C157-C175 at the base of the head subdomain identifies this bond as the molecular zipper of the plasticity of hCD81LEL. We propose that this conformational dependence of hCD81LEL, which is finely tuned by pH and redox conditions, enables the virus-receptor interactions to diversely re-engage at endosomal conditions.
authors.affiliation: Structural Biology Unit, CIC bioGUNE, CIBERehd, Derio 48160, Spain.
authors.forename: Eva S
authors.initials: ES
authors.lastname: Cunha
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; Joint BSC-IRB Program in Computational Biology, Institute for Research in Biomedicine, Barcelona 08028, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Sfriso
authors.affiliation: Structural Biology Unit, CIC bioGUNE, CIBERehd, Derio 48160, Spain.
authors.forename: Adriana L
authors.initials: AL
authors.lastname: Rojas
authors.affiliation: IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, England, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Roversi
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona 08028, Spain; Joint BSC-IRB Program in Computational Biology, Institute for Research in Biomedicine, Barcelona 08028, Spain.
authors.forename: Adam
authors.initials: A
authors.lastname: Hospital
authors.affiliation: Joint BSC-IRB Program in Computational Biology, Institute for Research in Biomedicine, Barcelona 08028, Spain; Department of Biochemistry and Biomedicine, Faculty of Biology, University of Barcelona, Barcelona 08028, Spain.
authors.forename: Modesto
authors.initials: M
authors.lastname: Orozco
authors.affiliation: Structural Biology Unit, CIC bioGUNE, CIBERehd, Derio 48160, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao 48013, Spain. Electronic address: nabrescia@cicbiogune.es.
authors.forename: Nicola G A
authors.initials: NGA
authors.lastname: Abrescia
mesh_terms: D018360:Crystallography, X-Ray; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010084:Oxidation-Reduction; D011487:Protein Conformation; D060225:Tetraspanin 28 / Q000737:chemistry* / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000378:metabolism*; D053585:Virus Attachment; D053586:Virus Internalization
chemical_list: C554798:CD81 protein, human; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C091015:glycoprotein E2, Hepatitis C virus
keywords: X-ray crystallography; hepatitis C virus; molecular dynamics; receptor structure-function; tetraspanin CD81; virus entry