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Our laboratory has established conjugation with the Small Ubiquitin-like Modifier (SUMO) as an important regulatory mechanism in eukaryotes. By analysing the site of modification in a number of proteins we proposed a SUMO consensus modification site consisting of the sequence yKxE, where "y" represents a large hydrophobic amino acid and " x " represents any amino acid (figure 1b). We further demonstrated that this site constitutes a transferable signal that confers the ability to be modified with SUMO on proteins to which it is linked. In chordates there are 3 members of the SUMO family. Although SUMO-2 and SUMO-3 are 97% identical they share only 50% sequence identity with SUMO-1 and appear to be functionally distinct. We demonstrated that in contrast to SUMO-1, SUMO-2 and SUMO-3 could form poly-SUMO-2 chains.
Although we reported the existence of these chains in 2001, it is only recently that their function has been revealed. We recognised that the RING domain containing protein Rnf4 also contained multiple SUMO interaction motifs (SIMs) and demonstrated that it could function as a ubiquitin E3 ligase with a unique specificity for polySUMO chains. We further showed that Rnf4 is the ubiquitin ligase responsible for arsenic inducible, proteasomal degradation of the Promyelocytic Leukaemia (PML) protein. In Acute Promyelocytic Leukaemia (APL) the PML protein is fused to the Retinoic Acid Receptor and the disease can be effectively treated by arsenic administration. Arsenic induces modification of PML with SUMO and subsequent proteasomal degradation of PML. Our identification of Rnf4 as the E3 ligase responsible for the SUMO-dependent degradation of PML provides the molecular basis for the therapeutic action of a drug currently used to treat leukaemia (Tatham et al., 2008). Subsequent studies on arsenic and PML have established the dynamics and cell biology of this process (Geoffroy et al., 2010; Hattersley et al., 2011). The objective of present work is to determine the signal transduction pathway, activated by arsenic, which leads to increased SUMO modification of PML. X-ray crystallography and NMR spectroscopy are being employed to determine the structure of the ubiquitin E3 ligase Rnf4, bound to its poly SUMO substrate and its cognate E2 conjugating enzyme (Plechanovova et al., 2011,2012).
Although we reported the existence of these chains in 2001, it is only recently that their function has been revealed. We recognised that the RING domain containing protein Rnf4 also contained multiple SUMO interaction motifs (SIMs) and demonstrated that it could function as a ubiquitin E3 ligase with a unique specificity for polySUMO chains. We further showed that Rnf4 is the ubiquitin ligase responsible for arsenic inducible, proteasomal degradation of the Promyelocytic Leukaemia (PML) protein. In Acute Promyelocytic Leukaemia (APL) the PML protein is fused to the Retinoic Acid Receptor and the disease can be effectively treated by arsenic administration. Arsenic induces modification of PML with SUMO and subsequent proteasomal degradation of PML. Our identification of Rnf4 as the E3 ligase responsible for the SUMO-dependent degradation of PML provides the molecular basis for the therapeutic action of a drug currently used to treat leukaemia (Tatham et al., 2008). Subsequent studies on arsenic and PML have established the dynamics and cell biology of this process (Geoffroy et al., 2010; Hattersley et al., 2011). The objective of present work is to determine the signal transduction pathway, activated by arsenic, which leads to increased SUMO modification of PML. X-ray crystallography and NMR spectroscopy are being employed to determine the structure of the ubiquitin E3 ligase Rnf4, bound to its poly SUMO substrate and its cognate E2 conjugating enzyme (Plechanovova et al., 2011,2012).
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Papers共 357 篇Author StatisticsCo-AuthorSimilar Experts
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biorxiv(2024)
Marta Agostinho, Vera Santos,Fernando Ferreira, Rafael Costa,Joana Cardoso,Inês Pinheiro,José Rino,Ellis Jaffray,Ronald T. Hay,João Ferreira
crossref(2023)
PLoS pathogensno. 7 (2023): e1011477-e1011477
Emil P. T. Hertz, Ignacio Alonso-de Vega,Thomas Kruse, Yiqing Wang,Ivo A. Hendriks,Anna H. Bizard, Ania Eugui-Anta,Ronald T. Hay,Michael L. Nielsen,Jakob Nilsson,Ian D. Hickson,Niels Mailand
Nature structural & molecular biologyno. 9 (2023): 1303-1313
Marta Agostinho, Vera Santos,Fernando Ferreira, Rafael Costa,Joana Cardoso,Inês Pinheiro,José Rino,Ellis Jaffray,Ronald T. Hay,João Ferreira
crossref(2023)
Julio C.Y. Liu,Leena Ackermann,Saskia Hoffmann, Zita Gál,Ivo A. Hendriks, Charu Jain, Louise Morlot,Michael H. Tatham,Gian-Luca McLelland,Ronald T. Hay,Michael Lund Nielsen,Thijn Brummelkamp,
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