The common phospholipid-binding activity of the N-terminal domains of PEX1 and VCP/p97

International Graduate School of Arts and Sciences, Yokohama City University, 1-7-29 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
FEBS Journal (Impact Factor: 4). 12/2006; 273(21):4959-71. DOI: 10.1111/j.1742-4658.2006.05494.x
Source: PubMed


PEX1 is a type II AAA-ATPase that is indispensable for biogenesis and maintenance of the peroxisome, an organelle responsible for the primary metabolism of lipids, such as beta-oxidation and lipid biosynthesis. Recently, we demonstrated a striking structural similarity between its N-terminal domain and those of other membrane-related AAA-ATPases, such as valosine-containing protein (p97). The N-terminal domain of valosine-containing protein serves as an interface to its adaptor proteins p47 and Ufd1, whereas the physiologic interaction partner of the N-terminal domain of PEX1 remains unknown. Here we found that N-terminal domains isolated from valosine-containing protein, as well as from PEX1, bind phosphoinositides. The N-terminal domain of PEX1 appears to preferentially bind phosphatidylinositol 3-monophosphate and phosphatidylinositol 4-monophosphate, whereas the N-terminal domain of valosine-containing protein displays broad and nonspecific lipid binding. Although N-ethylmaleimide-sensitive fusion protein, CDC48 and Ufd1 have structures similar to that of valosine-containing protein, they displayed lipid specificity similar to that of the N-terminal domain of PEX1 in the assays. By mutational analysis, we demonstrate that a conserved arginine surrounded by hydrophobic residues is essential for lipid binding, despite very low sequence similarity between PEX1 and valosine-containing protein.

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Available from: Toshiyuki Shimizu
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    • "While the N-terminal domains (NTD) of Pex1p are positioned on top of the rings, the N-terminal domains (NTD) of Pex6p fold back and are situated aside of the double ring, forming the vertices of an atypically triangular geometry when the complex is viewed from top. By interactions of the Pex6p NTD to Pex15p [77], the Pex1p–Pex6p-complex is possibly anchored at its vertices to the peroxisomal membrane, whereby the affinity of the Pex1p NTD to phospholipids might support the attachment to the membrane [155]. Interestingly, D1 and D2 domains of the subunits are tilted, allowing the NTD of Pex6p to contact the D2 domain of the adjacent Pex1p subunit [76] [87]. "
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    ABSTRACT: Mutations in the PEX1 gene, which encodes a protein required for peroxisome biogenesis, are the most common cause of the Zellweger spectrum diseases. The recognition that Pex1p shares a conserved ATP-binding domain with p97 and NSF led to the discovery of the extended family of AAA(+)-type ATPases. So far, four AAA(+)-type ATPases are related to peroxisome function. Pex6p functions together with Pex1p in peroxisome biogenesis, ATAD1/Msp1p plays a role in membrane protein targeting and a member of the LON-family of proteases is associated with peroxisomal quality control. This review summarizes the current knowledge on the AAA(+)-proteins involved in peroxisome biogenesis and function.
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    • "Although Cdc48 can bind ubiquitin on its own, how this activity contributes to a specific process is little known with more focus having been placed on the ubiquitin binding properties of Cdc48 cofactors. Also poorly characterized is Cdc48's binding to lipids [111], which may be critical to its function because Cdc48 is often attracted to various membranes (e.g., ER, autophagosome, Golgi, and mitochondria) decorated with lipids. Interestingly, like its archaeal counterpart, Cdc48 contains an HbYX motif that could be docked onto the core particle of the proteasome, raising an intriguing possibility that Cdc48 may cap on one end of the 20S core proteasome particle and recognize and thread substrates into the proteolytic chamber for destruction [112, 113], which may be challenging to 19S regulatory particles. "
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    ABSTRACT: Cdc48 (also called VCP and p97) is an abundant protein that plays essential regulatory functions in a broad array of cellular processes. Working with various cofactors, Cdc48 utilizes its ATPase activity to promote the assembly and disassembly of protein complexes. Here, we review key biological functions and regulation of Cdc48 in ubiquitin-related events. Given the broad employment of Cdc48 in cell biology and its intimate ties to human diseases (e.g., amyotrophic lateral sclerosis), studies of Cdc48 will bring significant insights into the mechanism and function of ubiquitin in health and diseases.
    Full-text · Article · Sep 2013
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    • "As depicted by Blue-Native PAGE analysis of cytosolic Pex1p from HEK293 cells, Pex1p is mostly in a homo-trimer, and less in a homo-hexamer. Crystal structure of the N-terminal domain of mouse Pex1p resembles valosin-containing protein (VCP/p97), another member of the AAA proteins [32] [33]. VCP/p97 forms a barrel-like homohexameric structure [34]. "
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    ABSTRACT: Peroxisome is a single-membrane organelle in eukaryotes. The functional importance of peroxisomes in humans is highlighted by peroxisome-deficient peroxisome biogenesis disorders such as Zellweger syndrome. Two AAA peroxins, Pex1p and Pex6p, are encoded by PEX1 and PEX6, the causal genes for PBDs of complementation groups 1 and 4, respectively. PEX26 responsible for peroxisome biogenesis disorders of complementation group 8 codes for C-tail-anchored type-II membrane peroxin Pex26p, the recruiter of Pex1p-Pex6p complexes to peroxisomes. Pex1p is targeted to peroxisomes in a manner dependent on ATP hydrolysis, while Pex6p targeting requires ATP but not its hydrolysis. Pex1p and Pex6p are most likely regulated in their peroxisomal localization onto Pex26p via conformational changes by ATPase cycle. Pex5p is the cytosolic receptor for peroxisome matrix proteins with peroxisome targeting signal type-1 and shuttles between the cytosol and peroxisomes. AAA peroxins are involved in the export from peroxisomes of Pex5p. Pex5p is ubiquitinated at the conserved cysteine11 in a form associated with peroxisomes. Pex5p with a mutation of the cysteine11 to alanine, termed Pex5p-C11A, abrogates peroxisomal import of proteins harboring peroxisome targeting signals 1 and 2 in wild-type cells. Pex5p-C11A is imported into peroxisomes but not exported, hence suggesting an essential role of the cysteine residue in the export of Pex5p.
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