title: Solution structure of a multifunctional DNA- and protein-binding motif of human Werner syndrome protein.
abstract: Werner syndrome (WS) is an autosomal recessive disease that results in premature aging. Mutations in the WS gene (WRN) result in a loss of expression of the WRN protein and predispose WS patients to accelerated aging. As a helicase and a nuclease, WRN is unique among the five human RecQ helicase family members and is capable of multiple functions involved in DNA replication, repair, recombination, and telomere maintenance. A 144-residue fragment of WRN was previously determined to be a multifunctional DNA- and protein-binding domain (DPBD) that interacts with structure-specific DNA and a variety of DNA-processing proteins. In addition, DPBD functions as a nucleolar targeting sequence of WRN. The solution structure of the DPBD, the first of a WRN fragment, has been solved by NMR. DPBD consists of a winged helix-like motif and an unstructured C-terminal region of approximately 20 aa. The putative DNA-binding surface of DPBD has been identified by using known structural and biochemical data. Based on the structural data and on the biochemical data, we suggest a surface on the DPBD for interacting with other proteins. In this structural model, a single winged helix domain binds to both DNA and other proteins. Furthermore, we propose that DPBD functions as a regulatory domain to regulate the enzymatic activity of WRN and to direct cellular localization of WRN through protein-protein interaction.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD 20742, USA. jhu1@umail.umd.edu
authors.forename: Jin-Shan
authors.initials: JS
authors.lastname: Hu
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Feng
authors.forename: Wangyong
authors.initials: W
authors.lastname: Zeng
authors.forename: Guang-Xin
authors.initials: GX
authors.lastname: Lin
authors.forename: Xu Guang
authors.initials: XG
authors.lastname: Xi
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D004247:DNA / Q000378:metabolism*; D004265:DNA Helicases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D053484:RecQ Helicases; D016415:Sequence Alignment; D000071657:Werner Syndrome Helicase
chemical_list: D004247:DNA; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase