Multiple Evolutionary Origins of Ubiquitous Cu2+ and Zn2+ Binding in the S100 Protein Family

• DOI: 10.1371/journal.pone.0164740
• Publication Date: 2016-10-20T17:43:11Z
• Authors: Lucas C. Wheeler; Micah T. Donor; James S. Prell; Michael J. Harms
• Keywords: Isothermal Titration Calorimetry; Protein family

The S100 proteins are a large family of signaling that play critical roles in biology and disease. Many bind Zn2+, Cu2+, and/or Mn2+ as part their biological functions; however, the evolutionary origins binding remain obscure. One key question is whether divalent transition metal ancestral, or instead arose independently on multiple lineages. To tackle this question, we combined phylogenetics with biophysical characterization modern proteins. We demonstrate an earlier origin for established subfamilies than previously believed, reveal widely distributed across tree. Using isothermal titration calorimetry, found Cu2+ Zn2+ common features family: full breadth human paralogs—as well two early-branching tunicate Oikopleura dioica—bind these metals μM affinity stoichiometries ranging from 1:1 to 3:1 (metal:protein). While consistent tree, structural responses quite variable. Further, mutational analysis modeling revealed occurs at different sites This over evolution protein family. Our work reveals pattern which overall phenotype constant feature proteins, even while site mechanism evolutionarily labile.