The N-terminal Region of the Ubiquitin Regulatory X (UBX) Domain-containing Protein 1 (UBXD1) Modulates Interdomain Communication within the Valosin-containing Protein p97.

Franziska Trusch, Anja Matena, Maja Vuk, Lisa Koerver, Helene Knaevelsrud, Paul S. Freemont, Hemmo Meyer, Peter Bayer (Corresponding Author)

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)


Valosin-containing protein/p97 is an ATP-driven protein segregase that cooperates with distinct protein cofactors to control various aspects of cellular homeostasis. Mutations at the interface between the regulatory N-domain and the first of two ATPase domains (D1 and D2) deregulate the ATPase activity and cause a multisystem degenerative disorder, inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia/amyotrophic lateral sclerosis. Intriguingly, the mutations affect only a subset of p97-mediated pathways correlating with unbalanced cofactor interactions and most prominently compromised binding of the ubiquitin regulatory X domain-containing protein 1 (UBXD1) cofactor during endolysosomal sorting of caveolin-1. However, how the mutations impinge on the p97-cofactor interplay is unclear so far. In cell-based endosomal localization studies, we identified a critical role of the N-terminal region of UBXD1 (UBXD1-N). Biophysical studies using NMR and CD spectroscopy revealed that UBXD1-N can be classified as intrinsically disordered. NMR titration experiments confirmed a valosin-containing protein/p97 interaction motif and identified a second binding site at helices 1 and 2 of UBXD1-N as binding interfaces for p97. In reverse titration experiments, we identified two distant epitopes on the p97 N-domain that include disease-associated residues and an additional interaction between UBXD1-N and the D1D2 barrel of p97 that was confirmed by fluorescence anisotropy. Functionally, binding of UBXD1-N to p97 led to a reduction of ATPase activity and partial protection from proteolysis. These findings indicate that UBXD1-N intercalates into the p97-ND1 interface, thereby modulating interdomain communication of p97 domains and its activity with relevance for disease pathogenesis. We propose that the polyvalent binding mode characterized for UBXD1-N is a more general principle that defines a subset of p97 cofactors.
Original languageEnglish
Pages (from-to)29414-29427
Number of pages14
JournalThe Journal of Biological Chemistry
Issue number49
Early online date16 Oct 2015
Publication statusPublished - 4 Dec 2015

Bibliographical note

This work was supported by Deutsche Forschungsgemeinschaft Collaborative Research Centre 1093 (to P. B. and H. M.). The authors declare that they have no conflicts of interest with the contents of this article.


  • ATPase
  • endosome
  • nuclear magnetic resonance (NMR)
  • protein structure
  • protein-protein interaction
  • UBXD1
  • p97


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