Abstract
p97 belongs to the functional diverse superfamily of AAA+ (ATPases Associated with diverse cellular Activities) ATPases and is characterized by an N-terminal regulatory domain and two stacked hexameric ATPase domains forming a central protein conducting channel. p97 is highly versatile and has key functions in maintaining protein homeostasis including protein quality control mechanisms like the ubiquitin proteasome system (UPS) and autophagy to disassemble polyubiquitylated proteins from chromatin, membranes, macromolecular protein complexes and aggregates which are either degraded by the proteasome or recycled. p97 can use energy derived from ATP hydrolysis to catalyze substrate unfolding and threading through its central channel. The function of p97 in a large variety of different cellular contexts is reflected by its simultaneous association with different cofactors, which are involved in substrate recognition and processing, thus leading to the formation of transient multi-protein complexes. Dysregulation in protein homeostasis and proteotoxic stress are often involved in the development of cancer and neurological diseases and targeting the UPS including p97 in cancer is a well-established pharmacological strategy. In this chapter we will describe structural and functional aspects of the p97 interactome in regulating diverse cellular processes and will discuss the role of p97 in targeted cancer therapy.
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Acknowledgements
This work was supported by the Deutsche Forschungsgemeinschaft (Grant GRK2243/1) and the Rudolf Virchow Center for Experimental Biomedicine.
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Two recent cryo-EM structures (Cooney et al. 2019; Twomey et al. 2019) of Cdc48–cofactor complexes bound to either a polyubiquitylated model substrate or a native substrate visualized substrate/ubiquitin-derived residues in the central channel of Cdc48. Furthermore, the Cdc48 subunits adopted a helical arrangement consistent with the generalized hand-over-hand mechanism of protein translocation by AAA+ ATPases. Processing of ubiquitylated substrates was found to be initiated by ubiquitin unfolding and the insertion of its N-terminal segment into the central Cdc48 channel.
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Hänzelmann, P., Galgenmüller, C., Schindelin, H. (2019). Structure and Function of the AAA+ ATPase p97, a Key Player in Protein Homeostasis. In: Harris, J., Marles-Wright, J. (eds) Macromolecular Protein Complexes II: Structure and Function . Subcellular Biochemistry, vol 93. Springer, Cham. https://doi.org/10.1007/978-3-030-28151-9_7
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