Metal templated design of protein interfaces.
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.
Salgado
Eric N
EN
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0356, USA.
Ambroggio
Xavier I
XI
Brodin
Jeffrey D
JD
Lewis
Richard A
RA
Kuhlman
Brian
B
Tezcan
F Akif
FA
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
D008670:Metals; D046912:Multiprotein Complexes; D011506:Proteins; D015032:Zinc