| Structural highlights
Function
[RSP5_YEAST] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Component of a RSP5 ubiquitin ligase complex which specifies polyubiquitination and intracellular trafficking of the general amino acid permease GAP1 as well as other cell surface proteins like GAP1, FUR4, MAL61, PMA1 and STE2. The RSP5-BUL1/2 complex is also necessary for the heat-shock element (HSE)-mediated gene expression, nitrogen starvation GLN3-dependent transcription, pressure-induced differential regulation of the two tryptophan permeases TAT1 and TAT2 and sorting efficiency into multivesicular bodies. Also acts on RBP1. Plays a role in tolerance to o-dinitrobenzene. Involved in actin cytoskeleton organization and dynamics. Ubiquitinates the LAS17-binding proteins LSB1 and PIN3/LSB2 without directing them for degradation and affects LAS17 levels in a SLA1-dependent and LSB1/2-independent manner.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
HECT-family E3 ligases ubiquitinate protein substrates to control virtually every eukaryotic process and are misregulated in numerous diseases. Nonetheless, understanding of HECT E3s is limited by a paucity of selective and potent modulators. To overcome this challenge, we systematically developed ubiquitin variants (UbVs) that inhibit or activate HECT E3s. Structural analysis of 6 HECT-UbV complexes revealed UbV inhibitors hijacking the E2-binding site and activators occupying a ubiquitin-binding exosite. Furthermore, UbVs unearthed distinct regulation mechanisms among NEDD4 subfamily HECTs and proved useful for modulating therapeutically relevant targets of HECT E3s in cells and intestinal organoids, and in a genetic screen that identified a role for NEDD4L in regulating cell migration. Our work demonstrates versatility of UbVs for modulating activity across an E3 family, defines mechanisms and provides a toolkit for probing functions of HECT E3s, and establishes a general strategy for systematic development of modulators targeting families of signaling proteins.
System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes.,Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS Mol Cell. 2016 Apr 7;62(1):121-36. doi: 10.1016/j.molcel.2016.02.005. Epub 2016, Mar 3. PMID:26949039[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Yashiroda H, Kaida D, Toh-e A, Kikuchi Y. The PY-motif of Bul1 protein is essential for growth of Saccharomyces cerevisiae under various stress conditions. Gene. 1998 Dec 28;225(1-2):39-46. PMID:9931424
- ↑ Wang G, Yang J, Huibregtse JM. Functional domains of the Rsp5 ubiquitin-protein ligase. Mol Cell Biol. 1999 Jan;19(1):342-52. PMID:9858558
- ↑ Andoh T, Hirata Y, Kikuchi A. PY motifs of Rod1 are required for binding to Rsp5 and for drug resistance. FEBS Lett. 2002 Aug 14;525(1-3):131-4. PMID:12163175
- ↑ Kaida D, Toh-e A, Kikuchi Y. Rsp5-Bul1/2 complex is necessary for the HSE-mediated gene expression in budding yeast. Biochem Biophys Res Commun. 2003 Jul 11;306(4):1037-41. PMID:12821147
- ↑ Abe F, Iida H. Pressure-induced differential regulation of the two tryptophan permeases Tat1 and Tat2 by ubiquitin ligase Rsp5 and its binding proteins, Bul1 and Bul2. Mol Cell Biol. 2003 Nov;23(21):7566-84. PMID:14560004
- ↑ Crespo JL, Helliwell SB, Wiederkehr C, Demougin P, Fowler B, Primig M, Hall MN. NPR1 kinase and RSP5-BUL1/2 ubiquitin ligase control GLN3-dependent transcription in Saccharomyces cerevisiae. J Biol Chem. 2004 Sep 3;279(36):37512-7. Epub 2004 Jul 9. PMID:15247235 doi:10.1074/jbc.M407372200
- ↑ Pizzirusso M, Chang A. Ubiquitin-mediated targeting of a mutant plasma membrane ATPase, Pma1-7, to the endosomal/vacuolar system in yeast. Mol Biol Cell. 2004 May;15(5):2401-9. Epub 2004 Mar 12. PMID:15020711 doi:10.1091/mbc.E03-10-0727
- ↑ Kee Y, Lyon N, Huibregtse JM. The Rsp5 ubiquitin ligase is coupled to and antagonized by the Ubp2 deubiquitinating enzyme. EMBO J. 2005 Jul 6;24(13):2414-24. Epub 2005 Jun 2. PMID:15933713 doi:7600710
- ↑ Feller A, Boeckstaens M, Marini AM, Dubois E. Transduction of the nitrogen signal activating Gln3-mediated transcription is independent of Npr1 kinase and Rsp5-Bul1/2 ubiquitin ligase in Saccharomyces cerevisiae. J Biol Chem. 2006 Sep 29;281(39):28546-54. Epub 2006 Jul 24. PMID:16864574 doi:10.1074/jbc.M605551200
- ↑ Ren J, Kee Y, Huibregtse JM, Piper RC. Hse1, a component of the yeast Hrs-STAM ubiquitin-sorting complex, associates with ubiquitin peptidases and a ligase to control sorting efficiency into multivesicular bodies. Mol Biol Cell. 2007 Jan;18(1):324-35. Epub 2006 Nov 1. PMID:17079730 doi:10.1091/mbc.E06-06-0557
- ↑ Kaminska J, Spiess M, Stawiecka-Mirota M, Monkaityte R, Haguenauer-Tsapis R, Urban-Grimal D, Winsor B, Zoladek T. Yeast Rsp5 ubiquitin ligase affects the actin cytoskeleton in vivo and in vitro. Eur J Cell Biol. 2011 Dec;90(12):1016-28. doi: 10.1016/j.ejcb.2011.08.002. Epub, 2011 Oct 14. PMID:22000681 doi:10.1016/j.ejcb.2011.08.002
- ↑ Zhang W, Wu KP, Sartori MA, Kamadurai HB, Ordureau A, Jiang C, Mercredi PY, Murchie R, Hu J, Persaud A, Mukherjee M, Li N, Doye A, Walker JR, Sheng Y, Hao Z, Li Y, Brown KR, Lemichez E, Chen J, Tong Y, Harper JW, Moffat J, Rotin D, Schulman BA, Sidhu SS. System-Wide Modulation of HECT E3 Ligases with Selective Ubiquitin Variant Probes. Mol Cell. 2016 Apr 7;62(1):121-36. doi: 10.1016/j.molcel.2016.02.005. Epub 2016, Mar 3. PMID:26949039 doi:http://dx.doi.org/10.1016/j.molcel.2016.02.005
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