Prof. Dr. Anne Schütz from the Department of Chemistry, Ludwig-Maximilians-Universität München will held a talk about “Diverse Spectrum of Molecular Defects in Pathogenic Mutants of VCP/p97” during the MBExC Lecture on 5 June, 2025 at 10:00 a.m. at the Room 0.233, Ernst-Caspari-Haus (GZMB), Justus-von-Liebig-Weg 11, 37077 Göttingen

Abstract:
Valosin-containing protein (VCP/p97) plays a crucial role in a wide range of ubiquitin-dependent cellular processes, including protein degradation, membrane fusion, and DNA repair. Autosomal-dominant mutations in the VCP gene are linked to adult-onset disorders with heterogeneous phenotypes, collectively categorized under multisystem proteinopathy-1 (MSP1). This rare degenerative condition can affect the muscles, bones, and central nervous system, manifesting as frontotemporal dementia, amyotrophic lateral sclerosis, and parkinsonism [1]. More recently, VCP mutations have also been implicated in vacuolar tauopathies [2].
The diverse clinical presentations seen in patients with VCP-related disorders are reflected at the molecular level. Different mutant forms of VCP exhibit distinct defects that affect their structural dynamics, enzymatic activity, and nucleotide and cofactor binding [3,4]. In this presentation, we explore the molecular basis of these divergent dysfunctions in the AAA+ ATPase p97. By combining NMR spectroscopy, cryo-electron microscopy, and molecular dynamics simulations, we have developed a powerful toolkit that spans multiple time and length scales [5].

References
[1] M. Schiava et al., J. Neurol. Neurosurg. Psychiatry 93 (2022).
[2] N.F. Darwich et al., Science 370 (2020).
[3] A.K. Schütz et al. elife 5 (2016).
[4] A.K. Schütz et al. PNAS 5 (2017).
[5] M. Shein et al. Nat. Chem. 16 (2024).

Host: Dr. Eri Sakata UMG

Poster of the talk: