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The Conformational Dynamics of the Mitochondrial Hsp70 Chaperone

Von Martin Sikor (07.06.2010)

Proteins are the essential building blocks of cells. They do not only determine their structure but are involved in many biological functions like transport of nutrients and regulation of chemical reactions. Newly synthesized proteins, however, need to fold into a specific, functional three-dimensional form before being able to perform these tasks. Especially in the crowded environment of the cellular cytosol, chaperones are essential for many proteins to fold correctly.

Chaperones are classified into five different subgroups. The heat shock proteins 70 (Hsp70) are involved in a plethora of cellular functions ranging from folding to the remodeling of protein complexes and transport of proteins through membranes. We could for the first time follow the dynamical changes of the structure of a chaperone, the mitochondrial Hsp70 Ssc1, during its working cycle in real time and on the single molecule level. Ssc1 binds to an unfolded protein shielding it from the environment. This process is fueled by the hydrolysis of ATP to ADP.

The Conformational Dynamics of the Mitochondrial Hsp70 Chaperone[Bildunterschrift / Subline]: Left panel: Functional cycle of the mtHsp70 Chaperone. Starting from the ATP state in the center, it can either hydrolyze the ATP to ADP followed by release of ADP and rebinding of ATP (top) or bind the J protein Mdj1 and a non-native polypeptide (right). Mge1 then stimulates the excange of ADP with ATP on a ms timescale followed by release of the potentially folded substrate and the J protein on a timescale of seconds. Middle panel: Change of the fluroescence spectra in different states of the functional cycle. Right panel: Labeling sites to observe changes in the interdomain distance (318 - 425) and the opening state of the substrate binding lid (458 - 563) of DnaK.

We labeled specific positions on Ssc1 with different dye molecules and monitored the distance between the dyes using Förster Resonance Energy Transfer. This method allows conclusions on the structure of the chaperone. In the ATP state and the substrate bound state, its structure is very rigid, while in the ADP state, the chaperone has a more dynamic form sampling different conformations. This structural inhomogeneity results in functions distinguishing this Hsp70 from other chaperons, like the import of proteins into mitochondria.

Ssc1 is vital for cell survival, and understanding its function and dynamics will allow in a next step to understand how diseases like cancer, Alzheimer's or Parkinson's disease disturb proper folding of proteins.

  • since 2008
  • PhD student in the group of Prof. Don Lamb, LMU Munich
  • 2007
  • Simon Fraser University, Vancouver, Canada: Research assistant at Dr. Barbara Frisken’s lab
  • 2001 - 2007
  • Studies in physics, University of Augsburg, Germany

  • since 2008
  • Scholarship of the International Doktorate Programm NanoBioTechnology in the Elite Network of Bavaria

  • Koyeli Mapa, Martin Sikor, Volodymyr Kudryavtsev, Karin Waegemann, Stanislav Kalinin, Claus A.M. Seidel, Walter Neupert, Don C. Lamb, Dejana Mokranjac: "The Conformational Dynamics of the Mitochondrial Hsp70 Chaperone", Molecular Cell, 38,1-12 (2010).