FIGURE 1.

Parkin is an auto-inhibited E3 enzyme that requires structural rearrangement for activation. A, domain architecture of rat parkin, comprising a UBL domain, an ∼70-residue linker, and four domains of the RING family. Parkin is an RBR-type ubiquitin ligase with its catalytic center embedded in the most C-terminal RING2 domain (Cys⁴³¹ in rat parkin). The RING1 domain serves as an adapter platform for the incoming E2 enzyme. The yellow region represents a short REP, which functions in the auto-inhibition of parkin (7). B, quaternary structure of full-length parkin, drawn from PDB code 4K95 (7). Key sites are indicated. Important auto-inhibitory interactions in parkin include blockade of the catalytic cysteine by the RING0 domain and occlusion of the E2-binding site (blue) by the REP element. C and D, structural comparison of free parkin (C) from R. norvegicus (PDB code 4K95 (7)) and phosphoubiquitin-bound parkin (D) from P. humanus (PDB code 5CAW (19)). In both crystal structures, the catalytic cysteine is occluded by the RING0 domain. Protein representations were generated by PyMOL (Schrödinger, LLC.).