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OTUB1 inhibits E2. 34 / 34
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"The general features of the inhibition mechanism explain how OTUB1 inhibits other E2 enzymes in a non catalytic manner."
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"Further characterization of this mechanism demonstrated that OTUB1 directly binds and consequently inhibits a related subclass of E2 enzymes that include UBC13, the only known E2 that cooperates with RNF168 during the DNA damage response [23], [195]."
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"However, its inhibitory effect was higher than that of an OTUB1 N-terminal deletion mutant that does not inhibit the E2 activity of UBC13 (Nakada et al., 2010)."
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"In order to determine the structural basis for OTUB1 inhibition of E2 enzymes, and how ubiquitin allosterically regulates OTUB1 activity, we determined the structure of Caenorhabditis elegans OTUB1 (ceOTUB1) bound to human UBC13 at 1.8 A resolution (XREF_FIG), and a 2.35 A resolution quaternary complex structure containing ceOTUB1, Ubal and a UBC13 DCA ~ Ub conjugate generated with Ub G76C."
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"Resulting changes in substrate ubiquitination or downstream signaling pathways in cells expressing the mutant DUB are generally assumed to be due to the absence of deubiquitinating activity, with the notable exceptions of OTUB1, which inhibits E2 enzymes by a mechanism independent of catalytic activity 15, 16, 17 and OTUD4, which serves as a scaffold for USP enzymes 18."
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"In support of the possibility that the growth inhibition in yeast was due to E2 inhibition by OTUB1, we found that the OTUB1 DeltaN mutant, which is unable to inhibit E2 enzymes, failed to block growth (XREF_FIG)."
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"To investigate whether the inhibition of E2 by OTUB1 was the rate limiting step in its inhibition of SMAD3 polyubiquitylation in vitro, we set up an in vitro ubiquitylation assay with ubiquitin, E1, varying concentrations of E2, E3 and recombinant human SMAD3 in the presence or absence of 0.5 muM GST-OTUB1 (XREF_FIG)."
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"OTUB1 inhibits UBE2E1 autoubiquitination In previous studies in which OTUB1 has been shown to stabilize a substrate through its noncatalytic activity , OTUB1 inhibits the activity of an E2 that conjugates Lys-48-linked polyubiquitin to the substrate ( 21-26 ) ."
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"The ability of OTUB1 to bind to E2 enzymes and inhibit ubiquitin transfer in a manner that does not depend on OTUB1 catalytic activity was first discovered in studies of DNA damage signaling, in which OTUB1 inhibits the E2, UBE2N/UBC13 ( xref )."
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"Here we describe structural and biochemical studies elucidating how OTUB1 inhibits UBC13 and other E2 enzymes."
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"Interestingly, OTUB1 also inhibits other E2 enzymes including UBCH5A-C (UBE2D1-3) and UBCH6 (UBE2E1) 11 and has been found in complex with these E2 enzymes in cells XREF_BIBR, XREF_BIBR, although the biological significance of these observations is not yet known."
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"Further, UbcH5 in turn mediates Otub1 monoubiquitination and this monoubiquitination facilitates the Otub1 binding to UbcH5 and likely inhibits ubiquitin chain transfer [XREF_BIBR], providing a mechanism underlying the Otub1 inhibition of E2 activity."
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"In support of the possibility that the growth inhibition in yeast was due to E2 inhibition by OTUB1, we found that the OTUB1 ΔN mutant, which is unable to inhibit E2 enzymes, failed to block growth ( xref )."
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"A genetic system to dissect E2 inhibition by OTUB1."
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"On this basis, it has been proposed that OTUB1 inhibits the ability of E2 ~ Ub conjugates to participate in Ub transfer reactions and in building polyUb chains 2."
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"This E2 suppression by OTUB1 inhibits RNF168 mediated K63 polyubiquitylation in the DNA damage site ."
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"We next investigated whether OTUB1 inhibits E2 by preventing the conjugation of ubiquitin or the transfer of ubiquitin from E2 to E3."
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"This unique mechanism on how OTUB1 suppresses the activity of an E2 has been characterized by complementary biochemical and structural studies95-97 ."
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"OTUB1 interacts with UBC13 (UBE2N) and the UBE2D and UBE2E family E2 ubiquitin conjugating enzymes and inhibits their E2 activities in a DUB activity independent manner (Nakada et al., 2010; Sato et a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Intriguingly, OTUB1 inhibits UBC13 and UBE2D/2E family E2 conjugating enzymes in a DUB activity independent manner [XREF_BIBR]."
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"Occlusion of the E3 binding surface, along with the shielding of the Ub ~ UbcH5b ester linkage by OTUB1 likely accounts for the ability of OTUB1 to suppress E2 function."
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"We next investigated whether OTUB1 inhibits E2 by preventing the conjugation of ubiquitin or the transfer of ubiquitin from E2 to E3."
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"We have shown here that a subset of E2 enzymes markedly stimulate OTUB1 cleavage of Lys48 linked polyubiquitin (XREF_FIG) and that the same set of OTUB1-E2 interactions are required for both OTUB1 non catalytic inhibition of E2 enzymes and E2 stimulation of OTUB1 XREF_BIBR, XREF_BIBR."
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"Further characterization of this mechanism demonstrated that OTUB1 directly binds and consequently inhibits a related subclass of E2 enzymes that include UBC13, the only known E2 that cooperates with [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In previous studies in which OTUB1 has been shown to stabilize a substrate through its noncatalytic activity, OTUB1 inhibits the activity of an E2 that conjugates Lys-48–linked polyubiquitin to the substrate (21–26)."
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"Another OTU domain containing protein, otubain 1, uses residues other than the catalytic cysteine to inhibit the function of E2 enzymes, so it is possible that A20 utilizes its OTU domain in this manner 87."
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"17 OTUB1 also suppresses UBCH5 E2 enzyme and stabilizes the p53 protein."
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"These residues are important for OTUB1 inhibition of E2 activity 4 and are absent in OTUB2, which does not inhibit UBC13 4."
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"Further characterization of this mechanism demonstrated that OTUB1 directly binds and consequently inhibits a related subclass of E2 enzymes that include UBC13, the only known E2 that cooperates with RNF168 during the DNA damage response XREF_BIBR, XREF_BIBR."
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"Thus, the same E2 enzymes that are inhibited by OTUB1 when the E2 is charged with ubiquitin can stimulate OTUB1 when uncharged."
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"OTUB1 modulates p53 stability by suppressing the conjugation between MDM2 and its E2 enzyme, UbcH5."
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"To investigate whether the inhibition of E2 by OTUB1 was the rate-limiting step in its inhibition of SMAD3 polyubiquitylation in vitro , we set up an in vitro ubiquitylation assay with ubiquitin, E1, varying concentrations of E2, E3 and recombinant human SMAD3 in the presence or absence of 0.5 μM GST-OTUB1 ( xref )."
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"Here we review the current progress made towards the understanding of the complex regulation of the p53 tumor suppressor pathway by DUBs, the biological function of Otub1 including its positive regulation of p53, and the mechanistic insights into how Otub1 suppresses E2."
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"Discussion The ability of OTUB1 to bind to E2 enzymes and inhibit ubiquitin transfer in a manner that does not depend on OTUB1 catalytic activity was first discovered in studies of DNA damage signaling , in which OTUB1 inhibits the E2 , UBE2N / UBC13 ( 17 ) ."
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