The members of the research group Clemen are focused on the biochemical and cell biological analysis of proteins that have a role in the brain and in striated muscle, Annexin A7, Desmin, VCP (p97), Coronin-1C (3) and Coronin-7.
Annexin A7 is a member of the annexin protein family. It is expressed as a 47 and 51 kDa isoform, and is characterized by its ability to interact with phospholipids in the presence of Ca2+-ions and is thought to function in Ca2+-homeostasis. To address the largely unknown functions of Annexin A7 a knockout mouse model was generated previously by us.
Recent studies in desmin knock out mice have shown that the targeted ablation of desmin leads to pathological changes of the extrasarcomeric intermediate filament cytoskeleton, as well as structural and functional abnormalities of mitochondria in striated muscle. Heterozygous mutations of the human desmin gene on chromosome 2q35 cause a familial or sporadic form of skeletal myopathy frequently associated with cardiac abnormalities. Using transfection studies we show that desmin mutants are incapable of forming a desmin intermediate filament network .
Mutations in the VCP (valosin-containing protein, p97) gene on chromosome 9p13-p12 cause a late-onset form of autosomal dominant inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD). p97 is an ubiquitously expressed member of the AAA-ATPase family. It is involved in a wide variety of essential cellular processes comprising nuclear envelope reconstruction, the cell cycle, post-mitotic Golgi reassembly, suppression of apoptosis, DNA damage response and the ubiquitin proteasome protein and endoplasmic reticulum associated protein (ERAD) degradation systems. We investigated the pathological consequences of the heterozygous p97 mutations R93C, R155H, and R155C on human striated muscle.
Coronin proteins belong to the WD40-repeat proteins. They are mainly found at the submembraneous area, they bind F-actin in vitro, and most of the seven mammalian coronins have unclear roles. In mouse, all brain areas express coronin 3 during embryogenesis and the first postnatal stages. Expression in grey matter decreases postnatally, except for hippocampal pyramidal and dentate gyrus neurons, and cerebellar Purkinje cells, while levels in white matter increase in the course of myelination. We show that coronin 3 has roles in wound healing, protrusion formation, cell proliferation, cytokinesis, endocytosis, axonal growth, and secretion.
Figure 1: Clustal alignment of Human coronin 1 and 3 with mouse coronin 2 and 3. Identical amino acids are shaded dark gray, similar residues are light gray. Solid lines are WD repeats. Shown are only the first part of the comparison.
July 18, 2013
Institute for Biochemistry I, Joseph-Stelzmann-Strasse 52, D50931 Cologne
Suggestions and wishes: Gudrun Konertz