Structural and functional insights into the cofactor diversity of the human AAA ATPase p97

• Applicant: Dr. Petra Hänzelmann
• Subject Area: Structural Biology
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 222170367

The hexameric ATPase p97 participates in a variety of cellular processes including cell-cycle control, membrane fusion, transcriptional activation, DNA repair, apoptosis, autophagy as well as the ubiquitin proteasome system. p97 mediates these diverse cellular processes through the binding of multiple cofactors of which more than 20 have been identified so far. These proteins predominantly bind to the p97 N-terminal cofactor binding domain (N domain) but also to the unstructured Cterminus of p97. Interactions involving the N domain are mediated either via “ubiquitin regulatory X” (UBX) and ubiquitin-like binding domains (ULD), or through one of several short linear binding motifs. At this point the principles governing cofactor selectivity largely remain elusive. Deciphering the interactions will be crucial to understand the multiple physiological roles of p97 and its involvement in cancer as well as a wide variety of neurodegenerative disorders such as Parkinson’s and Huntington’s disease. Through a combination of biochemical, biophysical and structural approaches we will study the mechanisms underlying p97 cofactor binding and specificity, as well as the competition between cofactors or their synergistic binding to p97 via the following aims: (1) We will decipher the structural diversity of p97 cofactors recognizing its N domain. (2) We will study how the assembly of p97 with its various cofactors is organized. (3) We will structurally characterize p97- cofactor molecular machines.

• DFG Programme: Research Grants
• Participating Person: Professor Dr. Hermann Schindelin