RESUMO
In providing the cell with ATP generated by oxidative phosphorylation, the mitochondrial ADP/ATP carrier plays a central role in aerobic eukaryotic cells. Combining biochemical, genetic, and structural approaches contributes to understanding the molecular mechanism of this essential transport system, the dysfunction of which is implicated in neuromuscular diseases.
Assuntos
Translocases Mitocondriais de ADP e ATP/fisiologia , Doenças Neuromusculares/fisiopatologia , Animais , Atractilosídeo/análogos & derivados , Atractilosídeo/química , Atractilosídeo/farmacologia , Respiração Celular/fisiologia , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Humanos , Mitocôndrias Musculares/fisiologia , Translocases Mitocondriais de ADP e ATP/química , Translocases Mitocondriais de ADP e ATP/genéticaRESUMO
Import and export of metabolites through mitochondrial membranes are vital processes that are highly controlled and regulated at the level of the inner membrane. Proteins of the mitochondrial carrier family ( MCF ) are embedded in this membrane, and each member of the family achieves the selective transport of a specific metabolite. Among these, the ADP/ATP carrier transports ADP into the mitochondrial matrix and exports ATP toward the cytosol after its synthesis. Because of its natural abundance, the ADP/ATP carrier is the best characterized within MCF, and a high-resolution structure of one conformation is known. The overall structure is basket shaped and formed by six transmembrane helices that are not only tilted with respect to the membrane, but three of them are also kinked at the level of prolines. The functional mechanisms, nucleotide recognition, and conformational changes for the transport, suggested from the structure, are discussed along with the large body of biochemical and functional results.
Assuntos
Translocases Mitocondriais de ADP e ATP , Membranas Mitocondriais/metabolismo , Conformação Proteica , Trifosfato de Adenosina/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Humanos , Lipídeos/química , Translocases Mitocondriais de ADP e ATP/química , Translocases Mitocondriais de ADP e ATP/genética , Translocases Mitocondriais de ADP e ATP/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Nucleotídeos/química , Nucleotídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
The oligomerization state of the ADP/ATP carrier is an important issue in understanding the mechanism underlying nucleotide exchange across the inner mitochondrial membrane. The first high resolution structure obtained in the presence of carboxyatractyloside revealed a large cavity formed within a monomer in which the inhibitor is strongly bound. Whereas the protein-protein interactions implicated in the first crystal form are not biologically relevant, the new crystal form described herein, highlights favorable protein-protein interactions. The interactions are mediated by endogenous cardiolipins, which are tightly bound to the protein, two cardiolipins being sandwiched between the monomers on the matrix side. The putative dimerization interface evidenced here is consistent with other structural, biochemical or functional data published so far.
