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 (PTS1 and PTS2) sequences, whereas the transport of proteins destined for peroxisomal membranes is mediated by the membrane PTS signals (mPTS) and occurs independently of the matrix proteins by a distinct mechanism (reviewed in 5, 6 and 7). The import of peroxisomal matrix proteins can be divided into four main steps: 1) cargo recognition/transport; 2) docking of the cargo-loaded receptors on the peroxisomal membrane; 3) cargo release and translocation; and 4) receptor recycling (reviewed in 8, 7 and 6).

Pex6p and Pex1p are large AAA-ATPase family members (ATPases associated with a wide range of cellular activities) that contain two AAA-cassettes, each of which is characterized by Walker A (ATP binding) and Walker B (ATP hydrolysis) motifs (9, 2). Pex6p, Pex1p and several other peroxins (Pex4p, Pex15p and Pex22p) are involved in the ATP-dependent relocation of the PTS1 import receptor Pex5p from the peroxisomal membrane back to the cytosol after cargo release (reviewed in 7). Pex1p and Pex6p interact to form a stable heterodimer in the cytosol (3, 10). This interaction involves the N-terminal AAA-cassettes of both peroxins and requires ATP-binding but not hydrolysis by the C-terminal AAA-cassette of Pex1p (3, 11). The cytosolic Pex1p-Pex6p complex is then recruited to the peroxisomal membrane by direct interactions between Pex6p and Pex15p, a type II integral membrane protein that functions as a membrane anchor for the AAA-peroxin complex (12, 10). This interaction requires ATP binding by Pex6p and dissociation requires ATP hydrolysis, suggesting an ATP-dependent cycle of recruitment and release (12). The membrane-anchored form of the Pex1p-Pex6p complex mediates the dislocation of the docked, ubiquitinated Pex5p receptor from the peroxisomal membrane, resulting in either receptor recycling or degradation (4, 13).

PEX6 was originally identified using a positive selection procedure to isolate mutants with defective peroxisomal function (14). pex6 mutants are unable to utilize oleic acid as sole carbon source, mislocalize peroxisomal matrix proteins to the cytosol, and lack morphologically detectable peroxisomal structures (14).

The human peroxisome biogenesis disorders (PBDs; OMIM) are a group of genetically heterogeneous diseases with more than ten complementation groups that are characterized by severe mental retardation, neuronal, hepatic and renal abnormalities, and death in early infancy (15). 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. Pex6p is conserved from yeast to humans, and the human AAA-peroxins interact with each other similarly to the yeast proteins, suggesting conservation of function (16 and reviewed in 17). The human PEX6 gene (OMIM) is mutated in PBD patients in complementation group 4 (CG4) and the human ortholog is able to morphologically restore peroxisomes in peroxisome deficient human CG4 fibroblasts (18, 19).

Last updated: 2007-07-27