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 , .
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
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 .
Parkin is E3 ubiquitin-protein ligase which binds to E2
ubiquitin-conjugating enzymes, including UBCH7 and
UBCH8 , , .
Parkin plays protective role by sequestering misfolded
proteins by ubiquitinating itself and those proteins .
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 .
Furthermore, Parkin forms a complex with Heat shock protein
70 (HSP70) and STIP1 homology and U-box containing protein
CHIP enhances Parkin E3
enzymatic activity .
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 , , , , .
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 .
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 , .
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