Proteolysis Putative ubiquitin pathway

Putative ubiquitin pathway

Modulation of protein activities by ubiquitin-dependent modification regulates theturnover, degradation and function of many cellular proteins. Ubiquitin-activating enzyme(E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) catalyze theconjugation of the protein Ubiquitin to a variety of biologically significantprotein substrates for targeted degradation through the 26S proteasome, as well as fornonproteolytic regulation of their functions or subcellular localizations [1], [2].

Ubiquitin in ATP -dependent manner is first attached to E1ubiquitin-activating enzyme, such as UBE1. The activated Ubiquitin is thentransferred to E2 ubiquitin-conjugating enzyme, such as UBCH6, UBCH7,UBCH8, and UBE2D1. Subsequent reaction is catalysed by E3 ubiquitinligase, such as Parkin, TNF receptor-associated factor 6 ( TRAF6 ), andCul1/Rbx1 E3 ligase complex. The latter is composed of Cullin 1,RING-box protein 1 and S-phase kinase-associated proteins 1 and 2 ( SKP1and SKP2 ). E3 ubiquitin ligase recognizes the protein substrate, recruitsE2-ubiquitin complex, and catalyzes Ubiquitin transfer from E2 to substrate. Asingle run of the reaction causes monoubiquitination of a target protein that couldchange its function. Multiple runs of the reaction lead to polyubiquitination of thesubstrate. Polyubiquitinated proteins can either be activated (through K63 linkage), orrecognized and degraded by the 26S proteasome (through K48 linkage). The fate of themodified protein is defined by the way ubiquitin moieties are linked to each other [1].

Parkin is E3 ubiquitin-protein ligase which binds to E2 ubiquitin-conjugatingenzymes, including UBCH7 and UBCH8 [3], [4],[5]. Parkin plays protective role by sequestering misfolded proteinsby ubiquitinating itself and those proteins [6].

Parkin can interact with two known components of E3 ligase complexes, F-box andWD repeat domain containing 7 ( FBXW7 ) and Cullin 1. FBXW7 andCullin 1 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 ). CHIP enhancesParkin E3 enzymatic activity [8].

Parkin recognizes misfolded proteins, such as Septin 5, Synphilin1 and Parkin-associated endothelin receptor-like receptor ( PAELR ), andcatalyzes their K48-polyubiquitination to promote the proteasomal degradation [5], [9], [10], [11], [12].CHIP, HSP70, Parkin, and PAELR form a complex in theendoplasmic reticulum. CHIP promotes the dissociation of HSP70 fromParkin and PAELR, thus facilitating Parkin-mediated PAELRubiquitination [8].

TRAF6 is also E3 ubiquitin ligase that functions with the ubiquitin conjugating(E2) complex consisting of Ubiquitin-conjugating enzyme E2 variant 1 ( UEV1A ) andUbiquitin-conjugating enzyme E2N ( UBC13 ) to catalyze the synthesis of K63-linkedpolyubiquitin chains on target proteins including TRAF6 itself [13],[14].

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