| Structural highlights
Disease
CHIP_HUMAN Cerebellar ataxia - hypogonadism. The disease is caused by mutations affecting the gene represented in this entry.
Function
CHIP_HUMAN E3 ubiquitin-protein ligase which targets misfolded chaperone substrates towards proteasomal degradation. Collaborates with ATXN3 in the degradation of misfolded chaperone substrates: ATXN3 restricting the length of ubiquitin chain attached to STUB1/CHIP substrates and preventing further chain extension. Ubiquitinates NOS1 in concert with Hsp70 and Hsp40. Modulates the activity of several chaperone complexes, including Hsp70, Hsc70 and Hsp90. Mediates transfer of non-canonical short ubiquitin chains to HSPA8 that have no effect on HSPA8 degradation. Mediates polyubiquitination of DNA polymerase beta (POLB) at 'Lys-41', 'Lys-61' and 'Lys-81', thereby playing a role in base-excision repair: catalyzes polyubiquitination by amplifying the HUWE1/ARF-BP1-dependent monoubiquitination and leading to POLB-degradation by the proteasome. Mediates polyubiquitination of CYP3A4. Ubiquitinates EPHA2 and may regulate the receptor stability and activity through proteasomal degradation.[1] [2] [3] [4] [5] [6] [7] [8]
Publication Abstract from PubMed
Recent evidence suggests that deletion of STUB1 horizontal line a pivotal negative regulator of interferon-gamma sensing horizontal line may potentially clear malignant cells. However, current studies rely primarily on genetic approaches, as pharmacological inhibitors of STUB1 are lacking. Identifying a tool compound will be a step toward validating the target in a broader therapeutic sense. Herein, screening more than a billion macrocyclic peptides resulted in STUB1 binders, which were further optimized by a structure-enabled in silico design. The strategy to replace the macrocyclic peptides' hydrophilic and solvent-exposed region with a hydrophobic scaffold improved cellular permeability while maintaining the binding conformation. Further substitution of the permeability-limiting terminal aspartic acid with a tetrazole bioisostere retained the binding to a certain extent while improving permeability, suggesting a path forward. Although not optimal for cellular study, the current lead provides a valuable template for further development into selective tool compounds for STUB1 to enable target validation.
Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1.,Ng S, Brueckner AC, Bahmanjah S, Deng Q, Johnston JM, Ge L, Duggal R, Habulihaz B, Barlock B, Ha S, Sadruddin A, Yeo C, Strickland C, Peier A, Henry B, Sherer EC, Partridge AW J Med Chem. 2022 Jul 19. doi: 10.1021/acs.jmedchem.2c00406. PMID:35853179[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ballinger CA, Connell P, Wu Y, Hu Z, Thompson LJ, Yin LY, Patterson C. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol Cell Biol. 1999 Jun;19(6):4535-45. PMID:10330192
- ↑ Connell P, Ballinger CA, Jiang J, Wu Y, Thompson LJ, Hohfeld J, Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat Cell Biol. 2001 Jan;3(1):93-6. PMID:11146632 doi:http://dx.doi.org/10.1038/35050618
- ↑ Jiang J, Ballinger CA, Wu Y, Dai Q, Cyr DM, Hohfeld J, Patterson C. CHIP is a U-box-dependent E3 ubiquitin ligase: identification of Hsc70 as a target for ubiquitylation. J Biol Chem. 2001 Nov 16;276(46):42938-44. Epub 2001 Sep 13. PMID:11557750 doi:http://dx.doi.org/10.1074/jbc.M101968200
- ↑ Peng HM, Morishima Y, Jenkins GJ, Dunbar AY, Lau M, Patterson C, Pratt WB, Osawa Y. Ubiquitylation of neuronal nitric-oxide synthase by CHIP, a chaperone-dependent E3 ligase. J Biol Chem. 2004 Dec 17;279(51):52970-7. Epub 2004 Oct 4. PMID:15466472 doi:http://dx.doi.org/10.1074/jbc.M406926200
- ↑ Pabarcus MK, Hoe N, Sadeghi S, Patterson C, Wiertz E, Correia MA. CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases. Arch Biochem Biophys. 2009 Mar 1;483(1):66-74. doi: 10.1016/j.abb.2008.12.001., Epub 2008 Dec 10. PMID:19103148 doi:10.1016/j.abb.2008.12.001
- ↑ Annamalai B, Liu X, Gopal U, Isaacs JS. Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis. Mol Cancer Res. 2009 Jul;7(7):1021-32. doi: 10.1158/1541-7786.MCR-08-0582. Epub, 2009 Jun 30. PMID:19567782 doi:http://dx.doi.org/10.1158/1541-7786.MCR-08-0582
- ↑ Parsons JL, Tait PS, Finch D, Dianova II, Edelmann MJ, Khoronenkova SV, Kessler BM, Sharma RA, McKenna WG, Dianov GL. Ubiquitin ligase ARF-BP1/Mule modulates base excision repair. EMBO J. 2009 Oct 21;28(20):3207-15. doi: 10.1038/emboj.2009.243. Epub 2009 Aug, 27. PMID:19713937 doi:10.1038/emboj.2009.243
- ↑ Matsumura Y, Sakai J, Skach WR. Endoplasmic reticulum protein quality control is determined by cooperative interactions between Hsp/c70 protein and the CHIP E3 ligase. J Biol Chem. 2013 Oct 25;288(43):31069-79. doi: 10.1074/jbc.M113.479345. Epub, 2013 Aug 29. PMID:23990462 doi:http://dx.doi.org/10.1074/jbc.M113.479345
- ↑ Ng S, Brueckner AC, Bahmanjah S, Deng Q, Johnston JM, Ge L, Duggal R, Habulihaz B, Barlock B, Ha S, Sadruddin A, Yeo C, Strickland C, Peier A, Henry B, Sherer EC, Partridge AW. Discovery and Structure-Based Design of Macrocyclic Peptides Targeting STUB1. J Med Chem. 2022 Jul 19. doi: 10.1021/acs.jmedchem.2c00406. PMID:35853179 doi:http://dx.doi.org/10.1021/acs.jmedchem.2c00406
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