Profile

Research in the Department of Cellular Biochemistry focuses on the mechanisms of protein folding in the cell with the long term goal to understand the mechanisms and the components involved in this fundamental process at the molecular level. The ribosomes of higher cells continuously synthesize thousands of different protein chains up to several hundred amino acids in length. In order to become functionally active, these newly-synthesized proteins must first fold into a well-defined three-dimensional conformation. Many proteins subsequently assemble into oligomeric complexes. Protein folding can occur spontaneously in vitro, based on the information contained in the amino acid sequence of the polypeptide chain. In the cell, however, many proteins require assistance by the machinery of molecular chaperones to reach their folded states efficiently and at a biologically relevant time scale. Molecular chaperones prevent misfolding and irreversible aggregation of newly-synthesized polypeptide chains. Misfolding and aggregation can be the cause of important neurodegenerative diseases, such as the prion diseases Huntington’s - or Alzheimer’s disease.
Using a combination of biochemical, biophysical and cell biological methods we are working on the following projects: The mechanism of various types of chaperone (Hsp70, Hsp90, chaperonins); the function of molecular chaperones during folding of newly-synthesized proteins on ribosomes; the effects of chaperones on the aggregation properties of prion proteins and polyglutamine proteins, such as Huntingtin. Significant progress could be made in all these areas. For example, in cooperation with Manajit Hayer-Hartl a new mechanism by which the cylindrical chaperonin complex GroEL-GroES of bacteria can accelerate protein folding was discovered. A new co-factor, Unc45, was described for the Hsp90 multichaperone-system, which mediates the interaction of the muscle protein myosin with Hsp90, thus defining myosin as a new substrate of this chaperone. The crystal structure of the ATPase domain of Hsp70 in complex with the nucleotide exchange factor Bag-1 was determined in a collaboration with Ismail Moarefi in the Department. Bag-1 is a newly discovered regulator targeting various substrate proteins of Hsp70 to protein degradation. A new assay system for the infectious prion agent in Bovine Spongiform Encephalopathy (BSE) was developed in collaboration with Jörg Tatzelt´s group. Furthermore, together with Erich Wanker´s group in Berlin we could show that the pharmacological induction of stress proteins in cell culture causes a strong inhibition of the formation of amyloid aggregates involved in neurodegenerative diseases.