title: Disruption of the M80-Fe ligation stimulates the translocation of cytochrome c to the cytoplasm and nucleus in nonapoptotic cells.
abstract: Native cytochrome c (cyt c) has a compact tertiary structure with a hexacoordinated heme iron and functions in electron transport in mitochondria and apoptosis in the cytoplasm. However, the possibility that protein modifications confer additional functions to cyt c has not been explored. Disruption of methionine 80 (M80)-Fe ligation of cyt c under nitrative stress has been reported. To model this alteration and determine if it confers new properties to cyt c, a cyt c mutant (M80A) was constitutively expressed in cells. M80A-cyt c has increased peroxidase activity and is spontaneously released from mitochondria, translocating to the cytoplasm and nucleus in the absence of apoptosis. Moreover, M80A models endogenously nitrated cyt c because nitration of WT-cyt c is associated with its translocation to the cytoplasm and nucleus. Further, M80A cyt c may up-regulate protective responses to nitrative stress. Our findings raise the possibility that endogenous protein modifications that disrupt the M80-Fe ligation (such as tyrosine nitration) stimulate nuclear translocation and confer new functions to cyt c in nonapoptotic cells.
authors.affiliation: Department of Medicine and Cellular Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Luiz C
authors.initials: LC
authors.lastname: Godoy
authors.forename: Cristina
authors.initials: C
authors.lastname: Muñoz-Pinedo
authors.forename: Laura
authors.initials: L
authors.lastname: Castro
authors.forename: Simone
authors.initials: S
authors.lastname: Cardaci
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Schonhoff
authors.forename: Michael
authors.initials: M
authors.lastname: King
authors.forename: Verónica
authors.initials: V
authors.lastname: Tórtora
authors.forename: Mónica
authors.initials: M
authors.lastname: Marín
authors.forename: Qian
authors.initials: Q
authors.lastname: Miao
authors.forename: Jian Fei
authors.initials: JF
authors.lastname: Jiang
authors.forename: Alexandr
authors.initials: A
authors.lastname: Kapralov
authors.forename: Ronald
authors.initials: R
authors.lastname: Jemmerson
authors.forename: Gary G
authors.initials: GG
authors.lastname: Silkstone
authors.forename: Jinal N
authors.initials: JN
authors.lastname: Patel
authors.forename: James E
authors.initials: JE
authors.lastname: Evans
authors.forename: Michael T
authors.initials: MT
authors.lastname: Wilson
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Green
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.forename: Joan B
authors.initials: JB
authors.lastname: Mannick
mesh_terms: D017209:Apoptosis; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000201:enzymology*; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D034741:RNA, Small Interfering
chemical_list: D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D045304:Cytochromes c; D007501:Iron