High impact information on CDC48

• Furthermore, Cdc48/p97-Ufd1-Npl4 directly binds to spindle assembly factors and regulates their interaction with microtubules at the end of mitosis [1].
• The AAA-ATPase Cdc48/p97 regulates spindle disassembly at the end of mitosis [1].
• We propose that the Ufe1 protein acts in the dual capacity of an organelle membrane fusion-associated SNARE by undergoing direct t-t-SNARE and Cdc48p interactions during organelle membrane fusion as well as a t-SNARE for vesicular traffic [2].
• Instead, ER membranes require a NSF-related ATPase, Cdc48p [2].
• Here we show that Cdc48p, a cell-cycle protein with homology to Sec18p, is required in ER fusion [3].

Biological context of CDC48

• Yeast can also be triggered into apoptosis by a mutation in CDC48 or by expression of mammalian bax [4].
• The CDC48 sequence encodes a protein of 92 kD that has an internal duplication of 200 amino acids and includes a nucleotide binding consensus sequence [5].
• With the noninvestigated exception of haptophytes a phylogenetically and mechanistically related system is apparently present in all chromalveolates with 4 membrane-bound plastids because amongst others, PPC-specific Derlins (Der1-like proteins), CDC48 and its cofactor Ufd1 were identified in the nuclear genomes of diatoms and apicomplexa [6].
• ORFD, an open reading frame adjacent to the CDC48 gene, is even more similar to HCS26 [7].
• Yeast Derlin Dfm1 interacts with Cdc48 and functions in ER homeostasis [8].

Anatomical context of CDC48

• The AAA ATPase Cdc48/p97 and its partners transport proteins from the ER into the cytosol [9].
• Yeast cell cycle protein CDC48p shows full-length homology to the mammalian protein VCP and is a member of a protein family involved in secretion, peroxisome formation, and gene expression [5].
• The involvement of Cdc48p in dislocation is underscored by the accumulation of ERAD substrates in the endoplasmic reticulum when Cdc48p fails to function, as monitored by activation of the unfolded protein response [10].
• We show the association of mammalian p97 and its yeast homologue Cdc48p in complexes with two respective ERAD substrates, secretory immunoglobulin M in B lymphocytes and 6myc-Hmg2p in yeast [10].
• VCP, the mammalian homolog of cdc48, is tyrosine phosphorylated in response to T cell antigen receptor activation [11].

Associations of CDC48 with chemical compounds

• This similarity suggests that CDC48p participates in a cell cycle function related to that of N-ethylmaleimide-sensitive fusion protein/Sec18p in Golgi transport [5].
• In addition, we show that Cdc48p interacts in the cytosol with the deglycosylation enzyme, PNGase, only when Cdc48p is associated with a misfolded glycoprotein [12].

Physical interactions of CDC48

• Herein, we demonstrate that Cdc48 interacts directly with the C-terminal PUL domain of Doa1 [13].
• Neither cytosolic chaperones nor Cdc48p/Ufd1p/Npl4p complex components or proteasome activity are required for ER exit, indicating that K28 retrotranslocation is mechanistically different from classical ER-associated protein degradation (ERAD) [14].
• Furthermore, Dfm1p interacts with Cdc48p through its SHP boxes, and so defines a new motif for interaction with this widely-employed AAA-ATPase [8].
• The membrane protein Ubx2 contains a UBX domain that interacts with Cdc48 and an additional UBA domain [15].
• Second, Cdc48 also binds Otu1, a deubiquitylation enzyme, which disassembles multiubiquitin chains [16].

Other interactions of CDC48

• DOA1 and CDC48 mutations are epistatic, suggesting that their interaction is physiologically relevant [13].
• We show that these two proteins are probably delivery factors for ubiquitinated ER substrates to the proteasome, following their removal from the membrane via the Cdc48-Ufd1-Npl4p complex [17].
• We have applied this element to analysis of the LEU2, RAD50, and CDC48 genes of Saccharomyces cerevisiae [18].
• Finally, sequence analysis indicated that the UPR-related and Cdc48p interaction functions of Dfm1p could be separated, implying this protein probably has numerous actions in the cell [8].
• Doa1 is a Cdc48 adapter that possesses a novel ubiquitin binding domain [13].

Analytical, diagnostic and therapeutic context of CDC48

• Both co-immunoprecipitation and two-hybrid assays demonstrated that Ufd3p is an in vivo ligand of Cdc48p, an essential ATPase required for the cell cycle progression and the fusion of endoplasmic reticulum membranes [19].

References