SUMMARY PARAGRAPH for PEX12
The biogenesis of peroxisomes requires a group of protein factors referred to as peroxins which are encoded by the PEX genes. Peroxisomal proteins are synthesized on free polyribosomes and imported posttranslationally. The transport of peroxisomal matrix proteins from the cytoplasm to the peroxisome is mediated by two peroxisome-targeting signal sequences (PTS1 and PTS2). Peroxisomal membrane proteins (PMPs) are imported independently of the matrix proteins by a distinct mechanism mediated by the membrane PTS signal (mPTS) (6, 7, 8, 9 and references therein).
Pex12p is an integral peroxisomal membrane protein required for peroxisome biogenesis and peroxisomal matrix protein import (3). Pex12p contains a degenerate RING finger domain of the C3HC4 type in its essential carboxy-terminus, and forms the translocation subcomplex of the peroxisomal import machinery with RING-finger peroxins Pex2p and Pex10p (4). Localization studies demonstrate that the N-terminus of Pex12p faces the peroxisomal lumen and the C-terminus faces the cytosol (2).
Two subcomplexes of the peroxisomal import machinery have been defined: the docking subcomplex comprises Pex14p, Pex17p, and Pex13p, while the translocation subcomplex contains Pex2p, Pex10p, and Pex12p. The proteins of the translocation complex expose their RING finger domains to the outer face of the peroxisomal membrane, and act downstream of Pex14p, Pex17p, and Pex13p during the peroxisomal protein import process (10). Association of both subcomplexes into a larger import complex requires Pex8p, an intraperoxisomal protein. Pex8p organizes the formation of the larger import complex from the trans side of the peroxisomal membrane and thus might enable functional communication between both sides of the membrane (10).
The pex12delta deletion strain fails to import peroxisomal matrix proteins through both the PTS1 and PTS2 pathways. Pex12p-deficient cells retain particular structures that contain peroxisomal membrane proteins consistent with the existence of peroxisomal membrane remnants, or "ghosts", indicating that pex12delta cells are not impaired in peroxisomal membrane biogenesis. In immunoisolation experiments, Pex12p was co-purified with the RING finger protein Pex10p, the PTS1 receptor Pex5p and the docking proteins for the PTS1 and the PTS2 receptors at the peroxisomal membrane, Pex13p and Pex14p (2).
The human peroxisome biogenesis disorders (PBDs) are a group of genetically heterogeneous diseases characterized by severe mental retardation, neuronal, hepatic and renal abnormalities, and death in early infancy (11). Clinical features of PBD patients vary, but all exhibit a defect in the import of one or more classes of peroxisomal matrix proteins. This cellular phenotype is shared by yeast pex mutants, and human orthologs of yeast PEX genes are defective in some groups of PBD patients (11, 3).
Pex12p in humans exhibits the same peroxisomal membrane localization as yeast Pex12p. PEX12 expression restores peroxisomal protein import in fibroblasts from PBD patients of complementation group 3 (CG3) and frameshift mutations in PEX12 have been detected in two unrelated CG3 patients. These data demonstrate that mutations in PEX12 are responsible for CG3 of the PBD and that PEX12 plays an essential role in peroxisomal matrix protein import (3). Mutations in PEX12 have also been associated with Zellweger syndrome.
Last updated: 2005-03-08