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.