Anne Schuetz
Department of Chemistry, University of Munich (LMU), Germany
Broad spectrum of molecular defects in pathogenic variants of the p97/VCP enzyme – insights from NMR, cryo-EM and MD simulations
The multifunctional AAA+ ATPase p97/VCP is a central regulator of cellular proteostasis, acting upstream of the proteasome to control protein quality and turnover. In recent years, p97 has emerged as a promising pharmacological target in cancer and neurodegenerative disease. Mutations in p97 are associated with a diverse group of degenerative disorders affecting the central nervous system, muscle, and bone [1,2]. More recently, p97 has also been implicated in early-onset developmental disorders [3].
p97 is a 540 kDa homohexamer, with each subunit composed of tandem ATPase domains and a substrate-recruiting domain. The coordinated action of these domains within the hexamer enables p97 to remodel and extract protein substrates in a highly regulated manner.
In this seminar, I will present our past [4-6] and recent [7,8] collaborative efforts that integrate NMR spectroscopy, cryo-electron microscopy (cryo-EM), and molecular dynamics (MD) simulations to dissect the molecular origins of defects in pathogenic p97 variants. Our results show that the diversity of disease manifestations observed in patients is mirrored at the molecular level, ranging from altered protein dynamics and disrupted allosteric communication to changes in redox sensitivity.
By systematically characterizing these pathogenic variants, we are also gaining sharper insight into the fundamental mechanisms that govern the function of wild-type p97. Our work highlights the power of combining structural and protein dynamics methods with computational approaches to understand the operation of large and complex molecular machines.
References
[1] Pfeffer et al. Genes 2022. doi.org/10.3390/genes13060963
[2] Darwich. Science 2020. doi.org/10.1126/science.aay8826
[3] Mah-Som et al. Am. J. Hum. Genet. 2023 doi.org/10.1016/j.ajhg.2023.10.007
[4] Schuetz et al. eLife 2026 doi.org/10.7554/elife.20143
[5] Schütz et al. Proc. Natl. Acad. Sci. USA 2017, 10.1073/pnas.1707974114
[6] Rydzek et al. J. Am. Chem. Soc. 2020. doi.org/10.1021/jacs.0c03180
[7] Shein et al. Nat. Chem. 2024. doi.org/10.1038/s41557-024-01440-0
[8] Rout et al. in submission. The vacuolar tauopathy-associated mutation D395G confers redox sensitivity to p97/VCP