6i2m

From Proteopedia
Revision as of 15:43, 13 March 2019 by OCA (talk | contribs)
Jump to navigation Jump to search

Crystal structure of vaccinia virus protein A55 BTB-Back domain in complex with human Cullin-3 N-terminusCrystal structure of vaccinia virus protein A55 BTB-Back domain in complex with human Cullin-3 N-terminus

Structural highlights

6i2m is a 2 chain structure with sequence from Human and Vaccw. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:KBTB1, VACWR180, A55R (VACCW), CUL3, KIAA0617 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CUL3_HUMAN] Pseudohypoaldosteronism type 2E. Defects in CUL3 are the cause of Pseudohypoaldosteronism type 2E (PHA2E) [MIM:614496]. An autosomal dominant disorder characterized by severe hypertension, hyperkalemia, hyperchloremia, hyperchloremic metabolic acidosis, and correction of physiologic abnormalities by thiazide diuretics.[1]

Function

[KBTB1_VACCW] Probable substrate-specific adapter of CUL3-containing E3 ubiquitin-protein ligases which mediate the ubiquitination and subsequent proteasomal degradation of host target proteins. [CUL3_HUMAN] Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1 (By similarity). The functional specificity of the BCR complex depends on the BTB domain-containing protein as the susbstrate recognition component. BCR(SPOP) is involved in ubiquitination of BMI1/PCGF4, H2AFY and DAXX, and probably GLI2 or GLI3. BCR(KLHL9-KLHL13) controls the dynamic behavior of AURKB on mitotic chromosomes and thereby coordinates faithful mitotic progression and completion of cytokinesis. BCR(KLHL12) is involved in ER-Golgi transport by regulating the size of COPII coats, thereby playing a key role in collagen export, which is required for embryonic stem (ES) cells division: BCR(KLHL12) acts by mediating monoubiquitination of SEC31 (SEC31A or SEC31B). BCR(KLHL3) acts as a regulator of ion transport in the distal nephron; possibly by mediating ubiquitination of SLC12A3/NCC. Involved in ubiquitination of cyclin E and of cyclin D1 (in vitro) thus involved in regulation of G1/S transition.[2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

BTB-Kelch proteins are substrate-specific adaptors for cullin-3 (Cul3) RING-box-based E3 ubiquitin ligases, mediating protein ubiquitylation for subsequent proteasomal degradation. Vaccinia virus encodes three BTB-Kelch proteins: A55, C2, and F3. Viruses lacking A55 or C2 have altered cytopathic effects in cultured cells and altered pathology in vivo Previous studies have shown that the ectromelia virus orthologue of A55 interacts with Cul3 in cells. We report that the N-terminal BTB-BACK (BB) domain of A55 binds directly to the Cul3 N-terminal domain (Cul3-NTD), forming a 2:2 complex in solution. We solved the structure of an A55BB/Cul3-NTD complex from anisotropic crystals diffracting to 2.3/3.7 A resolution in the best/worst direction, revealing that the overall interaction and binding interface closely resembles the structures of cellular BTB/Cul3-NTD complexes, despite low sequence identity between A55 and cellular BTB domains. Surprisingly, despite this structural similarity, the affinity of Cul3-NTD for A55BB was stronger than for cellular BTB proteins. Glutamate substitution of A55 residue Ile 48, adjacent to the canonical varphi-X-D/E Cul3-binding motif, reduced affinity of A55BB for Cul3-NTD by at least two orders of magnitude. Moreover, Ile 48 and the varphi-X-D/E motif are conserved in A55 orthologs from other poxviruses, but not in the vaccinia virus proteins C2 or F3. The high-affinity interaction between A55BB and Cul3-NTD suggests that, in addition to directing the Cul3-RING E3 ligase complex to degrade cellular/viral target proteins that are normally unaffected, A55 may also sequester Cul3 from cellular adaptor proteins, thereby protecting substrates of these cellular adaptors from ubiquitylation and degradation.

Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55.,Gao C, Pallett MA, Croll TI, Smith GL, Graham SC J Biol Chem. 2019 Feb 28. pii: RA118.006561. doi: 10.1074/jbc.RA118.006561. PMID:30819806[8]

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

References

  1. ↑ Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Valimaki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012 Jan 22;482(7383):98-102. doi: 10.1038/nature10814. PMID:22266938 doi:http://dx.doi.org/10.1038/nature10814
  2. ↑ Singer JD, Gurian-West M, Clurman B, Roberts JM. Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev. 1999 Sep 15;13(18):2375-87. PMID:10500095
  3. ↑ Maeda I, Ohta T, Koizumi H, Fukuda M. In vitro ubiquitination of cyclin D1 by ROC1-CUL1 and ROC1-CUL3. FEBS Lett. 2001 Apr 13;494(3):181-5. PMID:11311237
  4. ↑ Hernandez-Munoz I, Lund AH, van der Stoop P, Boutsma E, Muijrers I, Verhoeven E, Nusinow DA, Panning B, Marahrens Y, van Lohuizen M. Stable X chromosome inactivation involves the PRC1 Polycomb complex and requires histone MACROH2A1 and the CULLIN3/SPOP ubiquitin E3 ligase. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7635-40. Epub 2005 May 16. PMID:15897469 doi:0408918102
  5. ↑ Kwon JE, La M, Oh KH, Oh YM, Kim GR, Seol JH, Baek SH, Chiba T, Tanaka K, Bang OS, Joe CO, Chung CH. BTB domain-containing speckle-type POZ protein (SPOP) serves as an adaptor of Daxx for ubiquitination by Cul3-based ubiquitin ligase. J Biol Chem. 2006 May 5;281(18):12664-72. Epub 2006 Mar 8. PMID:16524876 doi:10.1074/jbc.M600204200
  6. ↑ Sumara I, Quadroni M, Frei C, Olma MH, Sumara G, Ricci R, Peter M. A Cul3-based E3 ligase removes Aurora B from mitotic chromosomes, regulating mitotic progression and completion of cytokinesis in human cells. Dev Cell. 2007 Jun;12(6):887-900. PMID:17543862 doi:http://dx.doi.org/S1534-5807(07)00119-0
  7. ↑ Jin L, Pahuja KB, Wickliffe KE, Gorur A, Baumgartel C, Schekman R, Rape M. Ubiquitin-dependent regulation of COPII coat size and function. Nature. 2012 Feb 22;482(7386):495-500. doi: 10.1038/nature10822. PMID:22358839 doi:http://dx.doi.org/10.1038/nature10822
  8. ↑ Gao C, Pallett MA, Croll TI, Smith GL, Graham SC. Molecular basis of cullin-3 (Cul3) ubiquitin ligase subversion by vaccinia virus protein A55. J Biol Chem. 2019 Feb 28. pii: RA118.006561. doi: 10.1074/jbc.RA118.006561. PMID:30819806 doi:http://dx.doi.org/10.1074/jbc.RA118.006561

6i2m, resolution 2.30Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=6i2m&oldid=3012029"