What happens when Pex5 is ubiquitinated by Pex2, Pex10, and Pex12?
Import receptor recycling distinguishes peroxisomes mitochondria requiring extraction shuttling receptor after cargo delivery. After releasing matrix cargo lumen transient pore Pex5 remains embedded peroxisomal membrane peripherally N-terminus facing cytosol partial retrotranslocation. Return cytosol new cycles membrane extraction requires ubiquitination generating handle AAA motor. Specialized peroxisomal E3 ligase complex RING proteins Pex2 Pex10 Pex12 heterotrimeric zinc coordinated embedded membrane associates cytosolic E2 Pex4 anchored membrane Pex22. Pex5 undergoes thioester monoubiquitination conserved cysteine 11 near N-terminus rather than canonical lysine. Monoubiquitinated cysteine provides high-affinity binding site mechanoenzymes Pex1 Pex6 heterohexameric AAA ATPases ring anchored membrane via Pex26 mammals Pex15 yeast consuming ATP thread polypeptide pull Pex5 cytosol. Cytosolic deubiquitinase USP9X removes ubiquitin resetting receptor competent another round. Polyubiquitination lysine residues targets compromised Pex5 proteasomal degradation via RADAR quality control when recycling stalls. Pex5 does not traffic lysosome proteolysis nor mitochondria import nor bind KDEL receptor; fate precisely regulated ubiquitin recycling essential matrix import continuity and organelle functionality maintenance.
Ref: Platta et al., Cell Cycle 2007: Pex5 monoubiquitination by Pex2/10/12 recycles receptor via Pex1/6.