title: Computation and Functional Studies Provide a Model for the Structure of the Zinc Transporter hZIP4.
abstract: Members of the Zrt and Irt protein (ZIP) family are a central participant in transition metal homeostasis as they function to increase the cytosolic concentration of zinc and/or iron. However, the lack of a crystal structure hinders elucidation of the molecular mechanism of ZIP proteins. Here, we employed GREMLIN, a co-evolution-based contact prediction approach in conjunction with the Rosetta structure prediction program to construct a structural model of the human (h) ZIP4 transporter. The predicted contact data are best fit by modeling hZIP4 as a dimer. Mutagenesis of residues that comprise a central putative hZIP4 transmembrane transition metal coordination site in the structural model alter the kinetics and specificity of hZIP4. Comparison of the hZIP4 dimer model to all known membrane protein structures identifies the 12-transmembrane monomeric Piriformospora indica phosphate transporter (PiPT), a member of the major facilitator superfamily (MFS), as a likely structural homolog.
authors.affiliation: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts 01609.
authors.forename: Sagar
authors.initials: S
authors.lastname: Antala
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195; Department of Biochemistry, University of Washington, Seattle, Washington 98195; Molecular and Cellular Biology Program, University of Washington, Seattle, Washington 98195.
authors.forename: Sergey
authors.initials: S
authors.lastname: Ovchinnikov
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195; Department of Biochemistry, University of Washington, Seattle, Washington 98195.
authors.forename: Hetunandan
authors.initials: H
authors.lastname: Kamisetty
authors.affiliation: Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195; Department of Biochemistry, University of Washington, Seattle, Washington 98195.
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.affiliation: Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, Massachusetts 01609. Electronic address: rdempski@wpi.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Dempski
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006801:Humans; D007501:Iron / Q000378:metabolism; D008958:Models, Molecular; D055503:Protein Multimerization; D014981:Xenopus; D015032:Zinc / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D002413:Cations, Divalent; C486791:SLC39A4 protein, human; D007501:Iron; D015032:Zinc
keywords: computer modeling; membrane biophysics; membrane protein; metal homeostasis; metal ion-protein interaction; protein evolution; transport metal; transporter; zinc