title: The proapoptotic G41S mutation to human cytochrome c alters the heme electronic structure and increases the electron self-exchange rate.
abstract: The naturally occurring G41S mutation to human (Hs) cytochrome (cyt) c enhances apoptotic activity based upon previous in vitro and in vivo studies, but the molecular mechanism underlying this enhancement remains unknown. Here, X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, and density functional theory (DFT) calculations have been used to identify the structural and electronic differences between wild-type (WT) and G41S Hs cyt c. S41 is part of the hydrogen bonding network for propionate 7 of heme pyrrole ring A in the X-ray structure of G41S Hs cyt c and, compared to WT, G41S Hs cyt c has increased spin density on pyrrole ring C and a faster electron self-exchange rate. DFT calculations illustrate an electronic mechanism where structural changes near ring A can result in electronic changes at ring C. Since ring C is part of the solvent-exposed protein surface, we propose that this heme electronic structure change may ultimately be responsible for the enhanced proapoptotic activity of G41S Hs cyt c.
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, New York 14627, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Liptak
authors.forename: Robert D
authors.initials: RD
authors.lastname: Fagerlund
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Ledgerwood
authors.forename: Sigurd M
authors.initials: SM
authors.lastname: Wilbanks
authors.forename: Kara L
authors.initials: KL
authors.lastname: Bren
mesh_terms: D017209:Apoptosis; D003067:Coenzymes / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D045304:Cytochromes c / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D004583:Electrons; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011487:Protein Conformation; D011789:Quantum Theory
chemical_list: D003067:Coenzymes; D006418:Heme; D045304:Cytochromes c