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Parkin

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Parkin

Domains: Ubl, RING0, RING1, IBR, REP, RING2.

Parkin is a protein of the RBR protein family.

1 Function
2 Disease
3 Relevance
4 Structural highlights

Function

Parkin is an E3 ubiquitin ligase involved in mitophagy via the Pink1-Parkin pathway. Parkin can also act as a transcription factor, downregulating, for instance, the expression of p53 and PS2, and upregulating the expression of PS1.

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.

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

Clicking will colour Parkin from N-terminal (bluer) to C-terminal (redder) residues. will highlight each domain of the protein.

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 maintains a compact , and together with the REP element, , prevents the E2 from binding to the RING1 domain. Phosphorylation of the 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. 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 .

References

Kumar, A., Aguirre, J.D., Condos, T.E., Martinez-Torres, R.J., Chaugule, V.K., Toth, R., Sundaramoorthy, R., Mercier, P., Knebel, A., Spratt, D.E., Barber, K.R., Shaw, G.S., Walden, H. Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis. (2015) Embo J. 34: 2506-2521 Duplan , E., Sevalle, J., Viotti, J., Goiranm T., Bauer, C., Renbaum, P., Levy-Lahad, E., Gautier, C. A., Corti, O., Leroudier, N., Checler, F., da Costa, C. A. (2013) Parkin differently regulates Presenilin-1 and Presenilin-2 functions by direct control of their promoter transcription. J. Mol. Biol. 5, 132-142.