Ca(2+) binding to c-state of adenine nucleotide translocase (ANT)-surrounding cardiolipins enhances (ANT)-Cys(56) relative mobility: a computational-based mitochondrial permeability transition study.
The oxidation of critical cysteines/related thiols of adenine nucleotide translocase (ANT) is believed to be an important event of the Ca(2+)-induced mitochondrial permeability transition (MPT), a process mediated by a cyclosporine A/ADP-sensitive permeability transition pores (PTP) opening. We addressed the ANT-Cys(56) relative mobility status resulting from the interaction of ANT/surrounding cardiolipins with Ca(2+) and/or ADP by means of computational chemistry analysis (Molecular Interaction Fields and Molecular Dynamics studies), supported by classic mitochondrial swelling assays. The following events were predicted: (i) Ca(2+) interacts preferentially with the ANT surrounding cardiolipins bound to the H4 helix of translocase, (ii) weakens the cardiolipins/ANT interactions and (iii) destabilizes the initial ANT-Cys(56) residue increasing its relative mobility. The binding of ADP that stabilizes the conformation "m" of ANT and/or cardiolipin, respectively to H5 and H4 helices, could stabilize their contacts with the short helix h56 that includes Cys(56), accounting for reducing its relative mobility. The results suggest that Ca(2+) binding to adenine nucleotide translocase (ANT)-surrounding cardiolipins in c-state of the translocase enhances (ANT)-Cys(56) relative mobility and that this may constitute a potential critical step of Ca(2+)-induced PTP opening.
Pestana
Cezar R
CR
Departamento de Física e Química, Toxicológicas e Bromatológicas, Universidade de São Paulo, 14040-903 Ribeirão Preto SP, Brazil.
Silva
Carlos H T P
CH
Pardo-Andreu
Gilberto L
GL
Rodrigues
Fernando P
FP
Santos
Antonio C
AC
Uyemura
Sérgio A
SA
Curti
Carlos
C
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002308:Cardiolipins / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D003198:Computer Simulation; D016572:Cyclosporine / Q000494:pharmacology; D003545:Cysteine / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D000226:Mitochondrial ADP, ATP Translocases / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects*; D000083162:Mitochondrial Permeability Transition Pore; D008933:Mitochondrial Swelling / Q000187:drug effects; D008956:Models, Chemical; D008958:Models, Molecular; D018384:Oxidative Stress; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D019802:Succinic Acid / Q000494:pharmacology
D002308:Cardiolipins; D007166:Immunosuppressive Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D000244:Adenosine Diphosphate; D016572:Cyclosporine; D000226:Mitochondrial ADP, ATP Translocases; D019802:Succinic Acid; D003545:Cysteine; D002118:Calcium