A novel dynein-type AAA+ protein with peroxisomal targeting signal type 2

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Peroxisomal matrix proteins are imported into peroxisomes in a process mediated by peroxisomal targeting signal (PTS) type 1 and 2. The PTS2 proteins are imported into peroxisomes after binding with Pex7p. Niwa et al. (A newly isolated Pex7-binding, atypical PTS2 protein P7BP2 is a novel dynein-type AAA+ protein. J Biochem 2018;164:437–447) identified a novel Pex7p-binding protein in CHO cells and characterized the subcellular distribution and molecular properties of the human homologue, ‘P7BP2’. Interestingly, P7BP2 possesses PTS2 at the NH2 terminal and six putative AAA+ domains. Another group has suggested that the protein also possesses mitochondrial targeting signal at the NH2 terminal. In fact, the P7BP2 expressed in mammalian cells is targeted to both peroxisomes and mitochondria. The purified protein from Sf9 cells is a monomer and has a disc-like ring structure, suggesting that P7BP2 is a novel dynein-type AAA+ family protein. The protein expressed in insect cells exhibits ATPase activity. P7BP2 localizes to peroxisomes and mitochondria, and has a common function related to dynein-type ATPases in both organelles.

Peroxisomal matrix proteins with PTS1 or PTS2 are recognized by the receptors Pex5p and Pex7p, respectively. The cargo-bound receptors associate with the peroxisomal membrane via a docking complex that is comprised of the core components Pex13p and Pex14p. After the docking of the cargo-loaded receptors, the cargo is translocated across the membrane and released inside the peroxisome. After cargo release into the peroxisomal lumen, the receptors are mono-ubiquitinated at the peroxisomal membrane by the RING protein subcomplex, Pex2p, Pex10p and Pex12p. After mono-ubiquitination, the PTS receptors are transported into the cytosol, a process mediated by the AAA+ ATPases Pex1p and Pex6p. After being exported back to the cytosol, PTS receptors are deubiquitinated and then reused in the next round of import. (B) Predicted domain structure of P7BP2 and its shorter form, P7BP2S. The number in each square shows the sequence number of the AAA+ domain. (C) Model of organization of dynein (the heavy chain) and midasin. NH2 terminal dynein associates with several different proteins, including the intermediate chain, light intermediate chain, light chain, certain regulators and the dynactin complex. Dynein interacts with cargo vesicles through an adaptor protein, while the microtubule-binding site moves on the microtubule through ATP binding and hydrolysis. The MIDAS domain at the COOH terminal of midasin is involved in the removal of the ribosome assembly factor Rsa4 from the pre-60S particle (i.e. Pix particles) by conformational change of the domain induced by ATP binding and hydrolysis of the AAA+ domain.

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