Pathway Map Details

Proteolysis_Putative ubiquitin pathway



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Object list (links open in MetaCore):

CHIP, Ubiquitin, UBCH6, UBC13, RING-box protein 1, UBCH7, UEV1A, UBCH8, Cullin 1, UBE2D1, PAELR, FBXW7, Hsp70, Synphilin 1, SKP1, ATP, Septin 5, Cul1/Rbx1 E3 ligase, Parkin, UBE1, TRAF6, MJD (ataxin-3), SKP2

Description:

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:

  1. Sun Y
    E3 ubiquitin ligases as cancer targets and biomarkers. Neoplasia (New York, N.Y.) 2006 Aug;8(8):645-54
  2. Newton K, Vucic D
    Ubiquitin ligases in cancer: ushers for degradation. Cancer investigation 2007 Sep;25(6):502-13
  3. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T
    Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature genetics 2000 Jul;25(3):302-5
  4. Imai Y, Soda M, Takahashi R
    Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. The Journal of biological chemistry 2000 Nov 17;275(46):35661-4
  5. Zhang Y, Gao J, Chung KK, Huang H, Dawson VL, Dawson TM
    Parkin functions as an E2-dependent ubiquitin- protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1. Proceedings of the National Academy of Sciences of the United States of America 2000 Nov 21;97(24):13354-9
  6. von Coelln R, Dawson VL, Dawson TM
    Parkin-associated Parkinson's disease. Cell and tissue research 2004 Oct;318(1):175-84
  7. Staropoli JF, McDermott C, Martinat C, Schulman B, Demireva E, Abeliovich A
    Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity. Neuron 2003 Mar 6;37(5):735-49
  8. Imai Y, Soda M, Hatakeyama S, Akagi T, Hashikawa T, Nakayama KI, Takahashi R
    CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Molecular cell 2002 Jul;10(1):55-67
  9. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R
    An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 2001 Jun 29;105(7):891-902
  10. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM
    Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nature medicine 2001 Oct;7(10):1144-50
  11. Yang Y, Nishimura I, Imai Y, Takahashi R, Lu B
    Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 2003 Mar 27;37(6):911-24
  12. Takahashi R, Imai Y
    Pael receptor, endoplasmic reticulum stress, and Parkinson's disease. Journal of neurology 2003 Oct;250 Suppl 3:III25-9
  13. Wullaert A, Heyninck K, Janssens S, Beyaert R
    Ubiquitin: tool and target for intracellular NF-kappaB inhibitors. Trends in immunology 2006 Nov;27(11):533-40
  14. Watters TM, Kenny EF, O'Neill LA
    Structure, function and regulation of the Toll/IL-1 receptor adaptor proteins. Immunology and cell biology 2007 Aug-Sep;85(6):411-9