6r8f

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Cryo-EM structure of the Human BRISC-SHMT2 complex

Structural highlights

6r8f is a 8 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 3.8Å
Experimental data:Check to display Experimental Data
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BRCC3_HUMAN Moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome. A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.[1]

Function

BRCC3_HUMAN Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).[2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Publication Abstract from PubMed

Serine hydroxymethyltransferase 2 (SHMT2) regulates one-carbon transfer reactions that are essential for amino acid and nucleotide metabolism, and uses pyridoxal-5'-phosphate (PLP) as a cofactor. Apo SHMT2 exists as a dimer with unknown functions, whereas PLP binding stabilizes the active tetrameric state. SHMT2 also promotes inflammatory cytokine signalling by interacting with the deubiquitylating BRCC36 isopeptidase complex (BRISC), although it is unclear whether this function relates to metabolism. Here we present the cryo-electron microscopy structure of the human BRISC-SHMT2 complex at a resolution of 3.8 A. BRISC is a U-shaped dimer of four subunits, and SHMT2 sterically blocks the BRCC36 active site and inhibits deubiquitylase activity. Only the inactive SHMT2 dimer-and not the active PLP-bound tetramer-binds and inhibits BRISC. Mutations in BRISC that disrupt SHMT2 binding impair type I interferon signalling in response to inflammatory stimuli. Intracellular levels of PLP regulate the interaction between BRISC and SHMT2, as well as inflammatory cytokine responses. These data reveal a mechanism in which metabolites regulate deubiquitylase activity and inflammatory signalling.

Metabolic control of BRISC-SHMT2 assembly regulates immune signalling.,Walden M, Tian L, Ross RL, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, George R, Ault JR, El Oualid F, Pawlowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA, Zeqiraj E Nature. 2019 May 29. pii: 10.1038/s41586-019-1232-1. doi:, 10.1038/s41586-019-1232-1. PMID:31142841[14]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Fisch P, Forster A, Sherrington PD, Dyer MJ, Rabbitts TH. The chromosomal translocation t(X;14)(q28;q11) in T-cell pro-lymphocytic leukaemia breaks within one gene and activates another. Oncogene. 1993 Dec;8(12):3271-6. PMID:8247530
  2. ↑ Dong Y, Hakimi MA, Chen X, Kumaraswamy E, Cooch NS, Godwin AK, Shiekhattar R. Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. Mol Cell. 2003 Nov;12(5):1087-99. PMID:14636569
  3. ↑ Chen X, Arciero CA, Wang C, Broccoli D, Godwin AK. BRCC36 is essential for ionizing radiation-induced BRCA1 phosphorylation and nuclear foci formation. Cancer Res. 2006 May 15;66(10):5039-46. doi: 10.1158/0008-5472.CAN-05-4194. PMID:16707425 doi:http://dx.doi.org/10.1158/0008-5472.CAN-05-4194
  4. ↑ Sobhian B, Shao G, Lilli DR, Culhane AC, Moreau LA, Xia B, Livingston DM, Greenberg RA. RAP80 targets BRCA1 to specific ubiquitin structures at DNA damage sites. Science. 2007 May 25;316(5828):1198-202. PMID:17525341 doi:http://dx.doi.org/316/5828/1198
  5. ↑ Shao G, Lilli DR, Patterson-Fortin J, Coleman KA, Morrissey DE, Greenberg RA. The Rap80-BRCC36 de-ubiquitinating enzyme complex antagonizes RNF8-Ubc13-dependent ubiquitination events at DNA double strand breaks. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3166-71. doi:, 10.1073/pnas.0807485106. Epub 2009 Feb 6. PMID:19202061 doi:http://dx.doi.org/10.1073/pnas.0807485106
  6. ↑ Cooper EM, Cutcliffe C, Kristiansen TZ, Pandey A, Pickart CM, Cohen RE. K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1. EMBO J. 2009 Mar 18;28(6):621-31. doi: 10.1038/emboj.2009.27. Epub 2009 Feb 12. PMID:19214193 doi:http://dx.doi.org/10.1038/emboj.2009.27
  7. ↑ Shao G, Patterson-Fortin J, Messick TE, Feng D, Shanbhag N, Wang Y, Greenberg RA. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 2009 Mar 15;23(6):740-54. doi: 10.1101/gad.1739609. Epub 2009 Mar 4. PMID:19261746 doi:http://dx.doi.org/10.1101/gad.1739609
  8. ↑ Feng L, Huang J, Chen J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 2009 Mar 15;23(6):719-28. doi: 10.1101/gad.1770609. Epub 2009 Mar 4. PMID:19261748 doi:10.1101/gad.1770609
  9. ↑ Wang B, Hurov K, Hofmann K, Elledge SJ. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 2009 Mar 15;23(6):729-39. Epub 2009 Mar 4. PMID:19261749 doi:http://dx.doi.org/gad.1770309
  10. ↑ Feng L, Wang J, Chen J. The Lys63-specific deubiquitinating enzyme BRCC36 is regulated by two scaffold proteins localizing in different subcellular compartments. J Biol Chem. 2010 Oct 1;285(40):30982-8. doi: 10.1074/jbc.M110.135392. Epub 2010 , Jul 22. PMID:20656690 doi:http://dx.doi.org/10.1074/jbc.M110.135392
  11. ↑ Zheng H, Gupta V, Patterson-Fortin J, Bhattacharya S, Katlinski K, Wu J, Varghese B, Carbone CJ, Aressy B, Fuchs SY, Greenberg RA. A BRISC-SHMT complex deubiquitinates IFNAR1 and regulates interferon responses. Cell Rep. 2013 Oct 17;5(1):180-93. doi: 10.1016/j.celrep.2013.08.025. Epub 2013, Sep 26. PMID:24075985 doi:http://dx.doi.org/10.1016/j.celrep.2013.08.025
  12. ↑ Yan K, Li L, Wang X, Hong R, Zhang Y, Yang H, Lin M, Zhang S, He Q, Zheng D, Tang J, Yin Y, Shao G. The deubiquitinating enzyme complex BRISC is required for proper mitotic spindle assembly in mammalian cells. J Cell Biol. 2015 Jul 20;210(2):209-24. doi: 10.1083/jcb.201503039. PMID:26195665 doi:http://dx.doi.org/10.1083/jcb.201503039
  13. ↑ Zeqiraj E, Tian L, Piggott CA, Pillon MC, Duffy NM, Ceccarelli DF, Keszei AF, Lorenzen K, Kurinov I, Orlicky S, Gish GD, Heck AJ, Guarne A, Greenberg RA, Sicheri F. Higher-Order Assembly of BRCC36-KIAA0157 Is Required for DUB Activity and Biological Function. Mol Cell. 2015 Sep 17;59(6):970-83. doi: 10.1016/j.molcel.2015.07.028. Epub 2015 , Sep 3. PMID:26344097 doi:http://dx.doi.org/10.1016/j.molcel.2015.07.028
  14. ↑ Walden M, Tian L, Ross RL, Sykora UM, Byrne DP, Hesketh EL, Masandi SK, Cassel J, George R, Ault JR, El Oualid F, Pawlowski K, Salvino JM, Eyers PA, Ranson NA, Del Galdo F, Greenberg RA, Zeqiraj E. Metabolic control of BRISC-SHMT2 assembly regulates immune signalling. Nature. 2019 May 29. pii: 10.1038/s41586-019-1232-1. doi:, 10.1038/s41586-019-1232-1. PMID:31142841 doi:http://dx.doi.org/10.1038/s41586-019-1232-1

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6r8f, resolution 3.80Å

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