Proteolysis - Putative ubiquitin pathway

Putative ubiquitin pathway

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

Ubiquitin in ATP-dependent manner is first attached to E1 ubiquitin-activating enzyme, such as UBE1. The activated Ubiquitin is then transferred to E2 ubiquitin-conjugating enzyme, such as UBCH6, UBCH7, UBCH8, and UBE2D1. Subsequent reaction is catalysed by E3 ubiquitin ligase, such as Parkin, TNF receptor-associated factor 6 (TRAF6), and Cul1/Rbx1 E3 ligase complex. The latter is composed of Cullin 1, RING-box protein 1 and S-phase kinase-associated proteins 1 and 2 (SKP1 and SKP2). E3 ubiquitin ligase recognizes the protein substrate, recruits E2-ubiquitin complex, and catalyzes Ubiquitin transfer from E2 to substrate. A single run of the reaction causes monoubiquitination of a target protein that could change its function. Multiple runs of the reaction lead to polyubiquitination of the substrate. Polyubiquitinated proteins can either be activated (through K63 linkage), or recognized and degraded by the 26S proteasome (through K48 linkage). The fate of the modified 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-conjugating enzymes, including UBCH7 and UBCH8 [3], [4], [5]. Parkin plays protective role by sequestering misfolded proteins by ubiquitinating itself and those proteins [6].

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

Parkin recognizes misfolded proteins, such as Septin 5, Synphilin 1 and Parkin-associated endothelin receptor-like receptor (PAELR), and catalyzes their K48-polyubiquitination to promote the proteasomal degradation [5], [9], [10], [11], [12]. CHIP, HSP70, Parkin, and PAELR form a complex in the endoplasmic reticulum. CHIP promotes the dissociation of HSP70 from Parkin and PAELR, thus facilitating Parkin-mediated PAELR ubiquitination [8].

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

References:

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