UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

Schuberth, Christian; Buchberger, Alexander

doi:10.1007/s00018-008-8072-8

Cited by 258 publications

(289 citation statements)

References 76 publications

Supporting

Mentioning

275

Contrasting

Order By: Relevance

“…p97 binds to several ERAD components, including Derlin-1, VIMP (SelS), UBXD2 (Erasin), and UBXD8, and recruits several ubiquitin-chain modifiers including E3 ligases (gp78, HRD1, etc. ), chain elongation factors (Ufd2, E4 ubiquitin ligase), and deubiquitinases (YOD1, Ataxin-3, VCIP135) (Liang et al 2006;Mueller et al 2008;Schuberth and Buchberger 2008;Ernst et al 2009). Ubiquitinated substrates are transferred to the proteasome by shuttle proteins, known as HR23A/B or Ubiquilin-1 (Rad23 and Dsk2 in yeast), which contain ubiquitinassociated (UBA) and ubiquitin-like (UBL) domains that bind to polyubiquitin chains and the proteasome subunits (Rpn10/13, Rpt5), respectively (Deveraux et al 1994;Lam et al 2002;Raasi and Wolf 2007;Husnjak et al 2008;Finley 2009;Lim et al 2009).…”

Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

View full text Add to dashboard Cite

The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

show abstract

Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

View full text Add to dashboard Cite

show abstract

“…For example, the AAA ϩ protein N-ethylmaleimidesensitive factor cofactor, ␣-SNAP, recruits N-ethylmaleimidesensitive factor to the SNARE complex and stimulates the ATPase activity of N-ethylmaleimide-sensitive factor for disassembly of the SNARE complex (11,12). Cdc48/p97 AAA ϩ ATPase regulates membrane fusion through interaction with its cofactor p47, and participates in the ER-associated degradation process by forming a complex with its cofactors, Ufd1 and Npl4 (68). Given that torsinA is a 332-amino acid protein with a 220-amino acid AAA ϩ ATPase homology domain and 40-amino acid hydrophobic regions (69), it seems particularly plausible that torsinA ATPase would use co-factor(s) to extend its binding repertoire for substrate recognition and function regulation.…”

Section: Discussionmentioning

confidence: 99%

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Giles

Chin

2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

Early onset generalized dystonia (DYT1) is an autosomal dominant neurological disorder caused by deletion of a single glutamate residue (torsinA ⌬E) in the C-terminal region of the AAA ؉ (ATPases associated with a variety of cellular activities) protein torsinA. The pathogenic mechanism by which torsinA ⌬E mutation leads to dystonia remains unknown. Here we report the identification and characterization of a 628-amino acid novel protein, printor, that interacts with torsinA. Printor co-distributes with torsinA in multiple brain regions and colocalizes with torsinA in the endoplasmic reticulum. Interestingly, printor selectively binds to the ATP-free form but not to the ATP-bound form of torsinA, supporting a role for printor as a cofactor rather than a substrate of torsinA. The interaction of printor with torsinA is completely abolished by the dystoniaassociated torsinA ⌬E mutation. Our findings suggest that printor is a new component of the DYT1 pathogenic pathway and provide a potential molecular target for therapeutic intervention in dystonia.Early onset generalized torsion dystonia (DYT1) is the most common and severe form of hereditary dystonia, a movement disorder characterized by involuntary movements and sustained muscle spasms (1). This autosomal dominant disease has childhood onset and its dystonic symptoms are thought to result from neuronal dysfunction rather than neurodegeneration (2, 3). Most DYT1 cases are caused by deletion of a single glutamate residue at positions 302 or 303 (torsinA ⌬E) of the 332-amino acid protein torsinA (4). In addition, a different torsinA mutation that deletes amino acids Phe 323 -Tyr 328(torsinA ⌬323-328) was identified in a single family with dystonia (5), although the pathogenic significance of this torsinA mutation is unclear because these patients contain a concomitant mutation in another dystonia-related protein, ⑀-sarcoglycan (6). Recently, genetic association studies have implicated polymorphisms in the torsinA gene as a genetic risk factor in the development of adult-onset idiopathic dystonia (7,8).TorsinA contains an N-terminal endoplasmic reticulum (ER) 3 signal sequence and a 20-amino acid hydrophobic region followed by a conserved AAA ϩ (ATPases associated with a variety of cellular activities) domain (9, 10). Because members of the AAA ϩ family are known to facilitate conformational changes in target proteins (11,12), it has been proposed that torsinA may function as a molecular chaperone (13,14). TorsinA is widely expressed in brain and multiple other tissues (15) and is primarily associated with the ER and nuclear envelope (NE) compartments in cells (16 -20). TorsinA is believed to mainly reside in the lumen of the ER and NE (17-19) and has been shown to bind lamina-associated polypeptide 1 (LAP1) (21), lumenal domain-like LAP1 (LULL1) (21), and nesprins (22). In addition, recent evidence indicates that a significant pool of torsinA exhibits a topology in which the AAA ϩ domain faces the cytoplasm (20). In support of this topology, torsinA is found in the...

show abstract

“…UBX domain containing proteins constitute the largest family of p97 cofactors [46,47]. A subset of UBX domain proteins is characterized by the presence of an ubiquitin-associated (UBA) domain, which mediates binding to ubiquitylated substrates [48,49].…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

“…These UBA-UBX proteins serve as prototypical substrate-recruiting cofactors or substrate ''adaptors" of p97. So far, 13 UBX domain-containing proteins have been identified in mammals, all of which, with the exception of UBXD1 (see below), have been demonstrated to bind to p97 [46,47,49]. In addition, the related UBXL domain has been identified in a few p97 cofactors including the NPL4 subunit of the heterodimeric UFD1-NPL4 cofactor [50] and the two DUBs OTU1/YOD1 [51] and VCIP135 [52].…”

Section: Ubx and Ubxl Domainsmentioning

confidence: 99%

“…The binding sequence is quite variable and typically found in unstructured regions of p97 cofactors. In mammals, the motif is found in the SEP (Shp, eyesclosed, p47) domain-containing UBX proteins p47, p37, UBXD4 and UBXD5, where it is located N-terminally of the UBX domain [46], to which it is connected via a mainly unstructured linker. Further mammalian members are the UBX protein TUG (also known as ASPL) [77], UFD1 [50], DVC1 (also called Spartan, a homolog of yeast Wss1), a proteolytic enzyme that functions in DNA repair coupled to DNA replication [67,78], and the Derlin proteins DER1 and DER2 involved in endoplasmic reticulum associated protein degradation (ERAD) [66,[79][80][81].…”

Section: Shp Box/bs1mentioning

confidence: 99%

See 1 more Smart Citation

Control of p97 function by cofactor binding

2015

View full text Add to dashboard Cite

Edited by Wilhelm JustKeywords: ATPases Associated with diverse cellular Activities p47 UFD1-NPL4 UBXD1 Inclusion Body Myopathy with Pagets disease of the bone and Fronto-temporal Dementia a b s t r a c t p97 (also known as Cdc48, Ter94, and VCP) is an essential, abundant and highly conserved ATPase driving the turnover of ubiquitylated proteins in eukaryotes. Even though p97 is involved in highly diverse cellular pathways and processes, it exhibits hardly any substrate specificity on its own. Instead, it relies on a large number of regulatory cofactors controlling substrate specificity and turnover. The complexity as well as temporal and spatial regulation of the interactions between p97 and its cofactors is only beginning to be understood at the molecular level. Here, we give an overview on the structural framework of p97 interactions with its cofactors, the emerging principles underlying the assembly of complexes with different cofactors, and the pathogenic effects of disease-associated p97 mutations on cofactor binding.

show abstract

UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

Cited by 258 publications

References 76 publications

Protein Folding and Quality Control in the ER

Protein Folding and Quality Control in the ER

Printor, a Novel TorsinA-interacting Protein Implicated in Dystonia Pathogenesis

Control of p97 function by cofactor binding

Contact Info

Product

Resources

About