title: Metal templated design of protein interfaces.
abstract: Metal coordination is a key structural and functional component of a large fraction of proteins. Given this dual role we considered the possibility that metal coordination may have played a templating role in the early evolution of protein folds and complexes. We describe here a rational design approach, Metal Templated Interface Redesign (MeTIR), that mimics the time course of a hypothetical evolutionary pathway for the formation of stable protein assemblies through an initial metal coordination event. Using a folded monomeric protein, cytochrome cb(562), as a building block we show that its non-self-associating surface can be made self-associating through a minimal number of mutations that enable Zn coordination. The protein interfaces in the resulting Zn-directed, D(2)-symmetrical tetramer are subsequently redesigned, yielding unique protein architectures that self-assemble in the presence or absence of metals. Aside from its evolutionary implications, MeTIR provides a route to engineer de novo protein interfaces and metal coordination environments that can be tuned through the extensive noncovalent bonding interactions in these interfaces.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0356, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Salgado
authors.forename: Xavier I
authors.initials: XI
authors.lastname: Ambroggio
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Brodin
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lewis
authors.forename: Brian
authors.initials: B
authors.lastname: Kuhlman
authors.forename: F Akif
authors.initials: FA
authors.lastname: Tezcan
mesh_terms: D055592:Biophysical Phenomena; D019020:Directed Molecular Evolution; D015195:Drug Design; D008670:Metals / Q000737:chemistry*; D008958:Models, Molecular; D046912:Multiprotein Complexes; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055503:Protein Multimerization; D055550:Protein Stability; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D015032:Zinc / Q000737:chemistry
chemical_list: D008670:Metals; D046912:Multiprotein Complexes; D011506:Proteins; D015032:Zinc