title: Imbalances in p97 co-factor interactions in human proteinopathy.
abstract: The ubiquitin-selective chaperone p97 is involved in major proteolytic pathways of eukaryotic cells and has been implicated in several human proteinopathies. Moreover, mutations in p97 cause the disorder inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD). The molecular basis underlying impaired degradation and pathological aggregation of ubiquitinated proteins in IBMPFD is unknown. Here, we identify perturbed co-factor binding as a common defect of IBMPFD-causing mutant p97. We show that IBMPFD mutations induce conformational changes in the p97 N domain, the main binding site for regulatory co-factors. Consistently, mutant p97 proteins exhibit strongly altered co-factor interactions. Specifically, binding of the ubiquitin ligase E4B is reduced, whereas binding of ataxin 3 is enhanced, thus resembling the accumulation of mutant ataxin 3 on p97 in spinocerebellar ataxia type 3. Our results suggest that imbalanced co-factor binding to p97 is a key pathological feature of IBMPFD and potentially of other proteinopathies involving p97.
authors.affiliation: Department of Molecular Cell Biology, Max Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Fernández-Sáiz
authors.forename: Alexander
authors.initials: A
authors.lastname: Buchberger
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D057180:Frontotemporal Dementia / Q000150:complications* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018979:Myositis, Inclusion Body / Q000150:complications* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010001:Osteitis Deformans / Q000150:complications* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D011506:Proteins / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D000074405:Valosin Containing Protein
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D050505:Mutant Proteins; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D025521:Tumor Suppressor Proteins; C491497:UFD1 protein, human; D000255:Adenosine Triphosphate; D043743:Ubiquitin-Protein Ligase Complexes; C473697:UBE4B protein, human; D044767:Ubiquitin-Protein Ligases; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein