Parkin

Parkin is a pleiotrpic protein protein of the RBR protein family that acts as an E3 ubiquitin ligase and as a transcription factor. It is encoded by the PARK2 gene, located in the human chromosome 6. Parkin is expressed naturally in an autoinhibited state and becomes active upon phosphorylation by the Pink1 protein (PTEN-induced kinase 1).

Function

Parkin is an E3 ubiquitin ligase involved in mitophagy via the Pink1-Parkin pathway. Pink1 is a kinase that phosphorilates Parkin's Ubl domain at Ser65 residue, changing its conformation and allowing it to exert its ubiquitin ligase function. Parkin can also act as a transcription factor, downregulating, for instance, the expression of p53 and PS2, and upregulating the expression of PS1. Besides mitochondria, parkin is known to ubiquitinate various substrates. As of 2013, about two dozen parkin substrates had been identified (Duplan et al., 2013).

Disease

Mutations in the Parkin gene are widely associated with recessive juvenile Parkinson's disease forms. Being involved in autophagy via ubiquitinylation and in transcriptional repression of important cell cycle and amyloidogenic genes, it is also implied in Alzheimer's disease forms and other neurodegenerative diseases.

Relevance

Parkin acts as a repressor for p53, which is an important cell cycle regulator, and as a repressor for PS2 and activator of PS1 expression, which are proteins involved in the γ-secretase complex, which is one of the components in the amyloidogenic pathway.

Structural highlights

Parkin's secondary structure reveals a compact, autoinhibited conformation. Ubl domain is made of 5 strands and 2 helices; RING0 domain contains 1 helix and 5 strands; RING1 domain is made of 5 strands and 2 helices; The IBR domain is composed solely of 3 beta strands; the REP element consists of an alpha-helix; and the RING2 domain is made of 1 alpha-helix and 4 beta-strands. The whole protein is made of 22 beta-strands and 7 alpha-helices. The largest interface in the protein is that between Ubl and the rest of parkin. The primary contact is between the Ubl (β3, β5) and RING1 (helix H1) domains, sustained mainly by hydrophobic interactions mediated by I44 and V70 of the Ubl domain and L266, V269 and T270 of the RING1 domain. The extent and nature of the Ubl/RING1 interface suggests it is important for autoinhibition of parkin. Several activating ARJP mutations occur in the Ubl domain. For example, R42P mutation disrupts the central salt bridge between R42 and D262.

Clicking here will highlight each domain of Parkin by color.

Parkin is a monomeric 465-residues long protein containing an Ubiquitin-like (Ubl) domain, a RING0 domain, a RING1 domain, an In Between Rings (IBR) domain, a repressor (REP) element and a RING2 domain. Parkin is produced by the cell in an autoinhibited state. The Ubl domain maintains a compact RING0-RING1 interface, and together with the REP element, , prevents the E2 from binding to the RING1 domain. Phosphorylation of the Ser65 residue in the Ubl domain leads to a change in conformation in the tertiary structure of the protein in the RING0-RING1 interface, which is optimized for pUb binding. This activation of the molecule leads to recruitment of E2 by the Ring1 domain, which carry charged ubiquitin and pass it to a catalytic Cys431 in the RING2 domain. However, both pUb and pUbl cannot be bound to parkin at the same time, which is consistent with the proposed allosteric loss of structure to the C-terminus of Helix H3 and IBR domain that would interfere with the Ubl-binding site.

Besides its ubiquitin-ligase activity, Parkin also acts as a transcription factor, modulating, for instance, TP53, PSEN1 and PSEN2. According to Duplan et al. (2013), this function comes from a multidomain centered around RING1-IBR-RING2.