title: A unique IBMPFD-related P97/VCP mutation with differential binding pattern and subcellular localization.
abstract: p97/VCP is a hexameric AAA type ATPase that functions in a variety of cellular processes such as endoplasmic reticulum associated degradation (ERAD), organelle biogenesis, autophagy and cell-cycle regulation. Inclusion body myopathy associated with Paget disease of the bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder which has been attributed to mutations in p97/VCP. Several missense mutations affecting twelve different amino acids have been identified in IBMPFD patients and some of them were suggested to be involved in the observed pathology. Here, we analyzed the effect of all twelve p97/VCP variants on ERAD substrates and their cofactor binding abilities. While all mutants cause ERAD substrate accumulation, P137L mutant p97/VCP differs from other IBMPFD mutants by having a unique solubility profile and subcellular localization. Intriguingly, although almost all mutants exhibit enhanced p47 and Ufd1-Npl4 binding, the P137L mutation completely abolishes p97/VCP interactions with Ufd1, Npl4 and p47, while retaining its gp78 binding. While recombinant R155C mutant protein consistently interacts with both Ufd1 and VIM of gp78, P137L mutant protein lost binding ability to Ufd1 but not to VIM in vitro. The differential impairments in p97/VCP interactions with its functional partners and function should help our understanding of the molecular pathogenesis of IBMPFD.
authors: Ege University, Faculty of Pharmacy, Biochemistry Department, Izmir, Turkey.
authors: Yalcin
authors: Y
authors: Erzurumlu
authors: Fadime Aydin
authors: FA
authors: Kose
authors: Oguz
authors: O
authors: Gozen
authors: Devrim
authors: D
authors: Gozuacik
authors: Eric A
authors: EA
authors: Toth
authors: Petek
authors: P
authors: Ballar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport; D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003067:Coenzymes / Q000378:metabolism; D017124:Conserved Sequence; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics; D057180:Frontotemporal Dementia / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009154:Mutation; D018979:Myositis, Inclusion Body / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010001:Osteitis Deformans / Q000235:genetics*; D018384:Oxidative Stress / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D021381:Protein Transport / Q000235:genetics; D011506:Proteins / Q000378:metabolism; D051381:Rats; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D003067:Coenzymes; D047908:Intracellular Signaling Peptides and Proteins; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; C491497:UFD1 protein, human; D025801:Ubiquitin; C553975:p37 protein, human; D000251:Adenosine Triphosphatases; C404942:p97 ATPase