title: A Mutation Identified in Neonatal Microcephaly Destabilizes Zika Virus NS1 Assembly in Vitro.
abstract: An unprecedented epidemic of Zika virus (ZIKV) infection had spread to South and Central America. ZIKV infection was recently confirmed by CDC (the Centers for Disease Control and Prevention) to cause neonatal microcephaly, which posed a significant public health emergency of international concern. No specific vaccines or drugs are currently available to fight ZIKV infection. ZIKV nonstructural protein 1 (NS1) plays an essential role in viral replication and immune evasion. We determined the crystal structure of ZIKV NS1172-352, which forms a head-to-head, symmetric dimer with a unique 14-stranded β-ladder conserved among flaviviruses. The assembly of the β-ladder dimer is concentration dependent. Strikingly, one pathogenic mutation T233A (NCBI accession no. KU527068), found in the brain tissue of infected fetus with neonatal microcephaly, is located at the dimer interface. Thr233, a unique residue found in ZIKV but not in other flaviviruses, organizes a central hydrogen bonding network at NS1 dimer interface. Mutation of Thr233 to Ala disrupts this elaborated interaction network, and destabilizes the NS1 dimeric assembly in vitro. In addition, our structural comparison of epitopes for protective antibody 22NS1, targeting West Nile Virus NS1, could potentially be valuable in understanding its anti-virus specificities and in the development of antibodies against ZIKV.
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.|Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, People's Republic of China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Liu
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.
authors.forename: Kailin
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Ji
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xie
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.|Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, People's Republic of China.
authors.forename: Zefang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.
authors.forename: Li-Zhi
authors.initials: LZ
authors.lastname: Mi
authors.affiliation: School of Life Sciences, Tianjin University, Tianjin 300072, People's Republic of China.|Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, People's Republic of China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D008831:Microcephaly / Q000175:diagnosis / Q000209:etiology*; D008958:Models, Molecular; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D055550:Protein Stability; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000071244:Zika Virus / Q000502:physiology*; D000071243:Zika Virus Infection / Q000150:complications* / Q000276:immunology / Q000821:virology*
chemical_list: D000914:Antibodies, Viral; D000939:Epitopes; C000621601:NS1 protein, zika virus; D017361:Viral Nonstructural Proteins