Descriptions

Parkin belongs to the RBR subfamily of E3 ubiquitin ligases that function by transferring Ub from an E2-conjugating enzyme to a substrate through an E3-Ub intermediate. Parkin contains an N-terminal ubiquitin-like (UbL) domain connected through a linker to four zinc-coordinating domains consisting of RING0, following by the RBR (RING1, In-Between-RING (IBR), RING2) module common to other E3 Ub ligases. RING1 contains an E2 binding site and RING2 contains a catalytic cysteine that is an acceptor for an ubiquitin from RING1-bound E2~Ub forming an intermediate (E3~Ub) that leads to substrate or autoubiquitination.
Structural studies revealed that Parkin, in its basal state, adopts an autoinhibited conformation with several distinct sites of inhibition. First, the UbL domain is bound to RING1 such that Ser65 is poorly accessible for phosphorylation by PINK1. Second, the Repressor Element of Parkin (REP) blocks the site of E2 Ub-conjugating enzyme binding on RING1. Finally, the RING0 domain binds to RING2, where it occludes the Cys431 Ub acceptor site. PINK1 stimulates parkin activity through phosphorylation of both Ub and parkin's UbL domain at an equivalent serine 65 position in sequence and structure. The phosphorylation of both the UbL domain and Ub are required to activate parkin by releasing the UbL domain, forming an extended structure needed to facilitate E2-Ub binding.

Accessory elements