Molekulare Ursachen des Mohr-Tranebjaerg-Syndromes

The molecular basis of the Mohr-Tranebjaerg syndrome: A structural and functional analysis of the proteins DDP1 and Tim13 Mohr-Tranebjaerg syndrome is a mitochondrial disorder caused by a defects in the biogenesis of the human TIM23 translocase Tim8 and Tim13 of yeast belong to a family of evolutionary conserved zinc finger proteins that are organised in hetero-oligomeric complexes in the mitochondrial intermembrane space (IMS). The TIM8-13 complex assists the import of Tim23, the major component of the translocase for matrix-targeted proteins. Mutations in DDP1/TIMM8A, the gene encoding the human homolog of Tim8, cause the Mohr-Tranebjaerg syndrome (MTS), a progressive neurodegenerative disorder. This work shows that DDP1 and human Tim13 are zinc binding proteins which together form a 70 kDa complex in the intermembrane space of human mitochondria. Similar to yeast, the human DDP1-hTim13 complex facilitates import of yeast and human Tim23. It has been additionally analysed the structural and functional consequences of a MTS-missense mutation (C66W) directly affecting the conserved Cys4 metal binding motif. In this connection the C66W mutation impairs the ability to bind zinc. As a consequence, the mutated DDP1 loses its ability to assemble into a hetero-oligomeric complex with its partner protein human Tim13. Thus, it was suggested that an assembly defect of DDP1 is the molecular basis of Mohr-Tranebjaerg syndrome in patients carrying the C66W mutation.

Level thesis:degree_level

thesis.doctoral

Grantor dc:publisher

Ludwig-Maximilians-Universität

Year

2003

Author dc:creator

• Rothbauer, Ulrich

Repository record source_url

https://edoc.ub.uni-muenchen.de/1640/

OAI identifier oai:identifier

oai:edoc.ub.uni-muenchen.de:1640