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Proteolysis Role of Parkin in the Ubiquitin-Proteasomal Pathway

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Proteolysis Role of Parkin in the Ubiquitin-Proteasomal Pathway

Role of Parkin in the Ubiquitin-Proteasomal Pathway

Parkin is E3-ubiquitin-protein ligase that ubiquitinates itself and specificsubstrate proteins playing a protective role by sequestering misfolded proteins [1].

E3 ligases are part of the cellular machinery that tags proteins with ubiquitin,thereby targeting them for degradation by the proteasome. Ubiquitination of proteinsoccurs through sequential steps catalyzed by ubiquitin-activating (E1), conjugating (E2),and ligase (E3) enzymes.

In the case of Parkin, the ubiquitin-conjugating enzymes UBCH7 andUBCH8 are the participating E2s [2], [3], [4]. Additionally, Parkin interacts with endoplasmic-reticulum-associatedE2s UBC6 and UBC7 [5].

Parkin has commonly been classified as a single-subunit E3 [6].However, Parkin has been reported to interact with two known components of E3ligase complexes, F-box and WD repeat domain containing 7 ( FBXW7 ) and Cullin1, which potentiate Parkin's ubiquitin ligase activity [7].Furthermore, Parkin forms a complex with Heat shock protein 70 ( HSP70 )and STIP1 homology and U-box containing protein 1 ( CHIP ), enhancing its E3enzymatic activity and its ability to inhibit cell death induced by unfolded proteinstress [8].

One of the Parkin substrates is Septin 5 [4]. It ispredominantly expressed in the nervous system, where it is associated with synapticvesicles [9].

Parkin also ubiquitinates Tubulin alpha and Tubulin beta andincreases their degradation. Microtubules are polymers of tubulin alpha/betaheterodimers. Misfolded tubulin monomers are highly toxic and quickly degraded [10].

Parkin associates with FBXW7 and Cullin 1 in the E3 ubiquitinligase complex to ubiquitinate Cyclin E [7].

Synphilin 1 is an interaction partner of Alpha-synuclein involved in theformation of Lewy bodies under Parkinson's disease [11], [12],[13]. Parkin interacts with and ubiquitinates Synphilin 1 andpromotes the ubiquitination of inclusion bodies [14].

The abundant unmodified form of Alpha-synuclein does not interact withParkin [14]. Nevertheless a rare O-glycosylated form ofAlpha-synuclein (alphaSp22) interacts with and is ubiquitinated by Parkin[15].

It was shown, that Synphilin 1 is ubiquitinated by other E3 ubiquitin-ligases,Seven in absentia homolog 1 and 2 ( SIAH1 and SIAH2 ), promoting itsdegradation by the ubiquitin-proteasome system [16]. SIAH1 andSIAH2 facilitate Synphilin 1 degradation more efficiently thanParkin or another E3 ligase, Ring finger protein 19A ( Dorfin ) [17], [18], [16].

SIAH1 and SIAH2 also induce monoubiquitination of Alpha-synucleinthat is not accompanied by proteasomal degradation of Alpha-synuclein, butrather, it promotes Alpha-synuclein aggregation and Lewy bodies' formation [16], [19], [20].

Parkin-associated endothelin receptor-like receptor ( PAELR ) is primarilyexpressed in oligodendrocytes, but also in a few distinct subpopulations of neurons.Unfolded and insoluble forms of PAELR can induce the selective degeneration ofdopaminergic neurons. Parkin ubiquitinates this insoluble form of PAELR,promoting its degradation, which results in the suppression of unfolded-protein-inducedcell death [5], [21], [22]. Under these conditions,Parkin apparently acts as part of the endoplasmic-reticulum-associated proteindegradation machinery, utilizing the endoplasmic-reticulum-associated E2 enzymes,UBC6 and UBC7 [1]. CHIP, co-chaperone of HSP70, can enhance Parkin-mediated ubiquitination of PAELR [8], [22].

Caspase-1 and Caspase-8 cleave and inactivate cellular Parkin[23].