RESPICHAIN
Financiado
Structure and mechanism of respiratory chain molecular machines
Eukaryotic life is made possible by energy production in mitochondria, where several large membrane protein complexes of the respiratory chain work in series to produce ATP. The structure and function of these complexes have been...
Eukaryotic life is made possible by energy production in mitochondria, where several large membrane protein complexes of the respiratory chain work in series to produce ATP. The structure and function of these complexes have been intensively studied over decades, but the mechanistic understanding is lacking due to their elaborate architecture. This proposal’s goal is to reveal the mechanism of energy transduction by the least understood of them: complex I, respiratory supercomplexes and transhydrogenase. Complex I is the largest respiratory enzyme, containing up to 45 subunits with a total mass of ~1 MDa. We have determined the first atomic structures of complex I from bacteria and mitochondria. Mammalian complex I usually exists as a supercomplex with complexes III2 and IV: we have determined the first architecture of this ~1.7 MDa physiological unit of respiration. The nicotinamide nucleotide transhydrogenase couples proton motive force to mitochondrial redox homeostasis, working in tandem with the respiratory chain. We recently determined the first structure of transhydrogenase but its coupling mechanism remains controversial. Huge conformational changes are envisaged but not yet observed. The mechanism of coupling between spatially separated electron transfer and proton translocation in complex I is also a mystery. It is likewise not known why respiratory complexes are organised into supercomplexes. We will tackle all these questions by an integrative approach, solving the atomic structures of different catalytic states of the complexes by applying the latest cryo-EM methods to these extremely challenging targets. The comparison of structures, complemented by functional and computational analyses, will reveal the mechanistic basis for the function of these molecular machines, solving fundamental questions in biology. As these enzymes are involved in many severe human disorders, the acquired knowledge will also be instrumental to tackle mitochondrial diseases.
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Duración del proyecto: 61 meses
Fecha Inicio: 2021-07-14
Fecha Fin: 2026-08-31
Fecha Fin: 2026-08-31
Línea de financiación: concedida
El organismo H2020 notifico la concesión del proyecto el día 2021-07-14
Línea de financiación objetivo
El proyecto se financió a través de la siguiente ayuda:
ERC-2020-ADG:
ERC ADVANCED GRANT
Cerrada
hace 4 años
Presupuesto
El presupuesto total del proyecto asciende a
2M€
Líder del proyecto
INSTITUTE OF SCIENCE AND TECHNOLOGY AUSTRIA
No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico
TRL
4-5
Perfil tecnológico
TRL
4-5
531.51K€ |
Participante