CUL4B

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CUL4B
Protein CUL4B PDB 2do7.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CUL4B, CUL-4B, MRXHF2, MRXS15, MRXSC, SFM2, cullin 4B
External IDs MGI: 1919834 HomoloGene: 2660 GeneCards: CUL4B
RNA expression pattern
PBB GE CUL4B 210257 x at fs.png

PBB GE CUL4B 202213 s at fs.png

PBB GE CUL4B 202214 s at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001079872
NM_003588
NM_001330624

NM_001110142
NM_028288

RefSeq (protein)

NP_001073341
NP_001317553
NP_003579

NP_001103612.1
NP_082564.3
NP_001103612
NP_082564

Location (UCSC) Chr X: 120.52 – 120.58 Mb Chr X: 38.53 – 38.58 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Cullin-4B is a protein that in humans is encoded by the CUL4B gene which is located on the X chromosome.[3][4] CUL4B has high sequence similarity with CUL4A, with which it shares certain E3 ubiquitin ligase functions. CUL4B is largely expressed in the nucleus and regulates several key functions including: cell cycle progression, chromatin remodeling and neurological and placental development in mice. In humans, CUL4B has been implicated in X-linked intellectual disability and is frequently mutated in pancreatic adenocarcinomas and a small percentage of various lung cancers. Viruses such as HIV can also co-opt CUL4B-based complexes to promote viral pathogenesis. CUL4B complexes containing Cereblon are also targeted by the teratogenic drug thalidomide.

Structure[edit]

Human CUL4B is 913 amino acids long and shares a high degree of sequence identity (84%) with CUL4A with the exception of its unique N-terminal region.[5] The extreme N-terminus of CUL4B is disordered and, currently, it is unclear what structural and functional qualities it possesses. CUL4B binds to the beta-propeller of the DDB1 adaptor protein which interacts with numerous DDB1-CUL4-Associated Factors (DCAFs). This interaction is crucial for the recruitment of substrates to the ubiquitin ligase complex. At the C-terminal end, CUL4B interacts with the RBX1/ROC1 protein via its RING domain. RBX1 is a core component of Cullin-RING ubiquitin ligase (CRL) complexes and functions to recruit E2 ubiquitin conjugating enzymes. Therefore, the C-terminus of CUL4B - along with RBX1 and activated E2 enzymes - compose the catalytic core of CRL4B complexes. CUL4B is also modified by covalent attachment of a NEDD8 molecule at a highly conserved lysine residue in the C-terminal region. This modification appears to induce conformational changes which promotes flexibility in the RING domain of cullin proteins and enhanced ubiquitin ligase activity.[6]

Functions[edit]

Cell cycle regulation and chromatin remodeling[edit]

CUL4B-based E3 ubiquitin ligase complexes often demonstrate overlapping activity with CUL4A-based complexes. Both CRL4 complexes utilize Cdt2 and the DNA processivity factor PCNA to induce the ubiquitination and degradation of replication licensing factor Cdt1 and cyclin-dependent kinase inhibitor p21 in a proteasome-dependent manner.[7][8] CRL4Cdt2 also degrades PCNA-bound PR-Set7/SET8, which is a histone 4 methyltransferase, and the p12 subunit of DNA polymerase δ, which is crucial for DNA replication.[9][10] As a result, CRL4 complexes are able to control the onset of DNA replication, chromatin remodeling and progression through the cell cycle.

Mammalian embryonic development[edit]

Loss of Cul4b in mice causes embryonic lethality and defects in placental development. The extra-embryonic tissue of these developing mice also showed increased rates of apoptosis and a decrease in cell proliferation. When Cul4b deletion was limited to the epiblast (only in Sox2-expressing tissue), it was possible to generate living mice.[11]

Neurological development[edit]

Mice that do not express CUL4B in epiblast tissue demonstrate normal brain morphology but decrease number of parvalbumin (PV)-positive GABAergic interneurons - particularly in the dentate gyrus.[12] In these mice, certain dendritic features of hippocampal neurons were also affected by Cul4b loss, which may explain the observed increases in epilectic susceptibility and spatial learning defects. These phenotypes resembled features seen in patients with X-linked intellectual disability (see below).

Clinical significance[edit]

X-linked intellectual disability[edit]

Loss-of-function CUL4B mutation events have been discovered in numerous patients with X-linked intellectual disability , which is characterized by aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus and tremor.[13][14][15] CUL4B mutations have also been associated with malformations of cortical development.[16]

Viral pathogenesis[edit]

After HIV infects a cell, the virus "hijacks" either the CUL4B-DDB1 complex or the CUL4A-DDB1 complex via the same mechanism. Essentially, HIV proteins such as Vpr and Vpx bind to VPRBP (a DDB1-binding substrate receptor protein) and induce the ubiquitination and degradation of SAMHD1 and UNG2 to promote viral replication.[17] These proteins are not degraded by CRL4 complexes in the absence of virus.

Cancer[edit]

According to data from The Cancer Genome Atlas, CUL4B is mutated in 21% of pancreatic carcinomas with a recurring truncating mutation at amino acid 143. CUL4B is also mutated or amplified in 3-5% of lung cancers. The significance of these observed mutations has not been determined.

Thalidomide treatment[edit]

In 2010, Ito et al. reported that Cereblon, a DCAF protein, was a major target of the teratogenic compound thalidomide.[18] Thalidomide and other derivatives such as pomalidomide and lenalidomide are known as immunomodulatory drugs (or IMiDs) and have been investigated as therapeutic agents for autoimmune diseases and several cancers - particularly myelomas. Recent reports show that IMiDs bind to CRL4CRBN and promote the degradation of IKZN1 and IKZN3 transcription factors, which are not normally targeted by CRL4 complexes.[19][20]

Interactions and substrates[edit]

Human CUL4B forms direct interactions with:

Human CUL4B-DDB1-RBX1 complexes promote the ubiquitination of:

protein is a CRL4 substrate only when directed by viral proteins
§protein is a CRL4 substrate only when directed by IMiDs

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
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  4. ^ "Entrez Gene: CUL4B cullin 4B". 
  5. ^ Fischer ES, Scrima A, Böhm K, Matsumoto S, Lingaraju GM, Faty M, Yasuda T, Cavadini S, Wakasugi M, Hanaoka F, Iwai S, Gut H, Sugasawa K, Thomä NH (Nov 2011). "The molecular basis of CRL4DDB2/CSA ubiquitin ligase architecture, targeting, and activation". Cell. 147 (5): 1024–39. doi:10.1016/j.cell.2011.10.035. PMID 22118460. 
  6. ^ Duda DM, Borg LA, Scott DC, Hunt HW, Hammel M, Schulman BA (Sep 2008). "Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation". Cell. 134 (6): 995–1006. doi:10.1016/j.cell.2008.07.022. PMC 2628631Freely accessible. PMID 18805092. 
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  8. ^ a b Nishitani H, Shiomi Y, Iida H, Michishita M, Takami T, Tsurimoto T (Oct 2008). "CDK inhibitor p21 is degraded by a proliferating cell nuclear antigen-coupled Cul4-DDB1Cdt2 pathway during S phase and after UV irradiation". The Journal of Biological Chemistry. 283 (43): 29045–52. doi:10.1074/jbc.M806045200. PMC 2662008Freely accessible. PMID 18703516. 
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  12. ^ Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ, Lin SW (Oct 2012). "Rescue of the genetically engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation". Human Molecular Genetics. 21 (19): 4270–85. doi:10.1093/hmg/dds261. PMID 22763239. 
  13. ^ Londin ER, Adijanto J, Philp N, Novelli A, Vitale E, Perria C, Serra G, Alesi V, Surrey S, Fortina P (2014). "Donor splice-site mutation in CUL4B is likely cause of X-linked intellectual disability". Am. J. Med. Genet. A. 164A (9): 2294–9. doi:10.1002/ajmg.a.36629. PMID 24898194. 
  14. ^ Zou Y, Liu Q, Chen B, Zhang X, Guo C, Zhou H, Li J, Gao G, Guo Y, Yan C, Wei J, Shao C, Gong Y (Mar 2007). "Mutation in CUL4B, which encodes a member of cullin-RING ubiquitin ligase complex, causes X-linked mental retardation". American Journal of Human Genetics. 80 (3): 561–6. doi:10.1086/512489. PMID 17273978. 
  15. ^ Tarpey PS, Raymond FL, O'Meara S, Edkins S, Teague J, Butler A, Dicks E, Stevens C, Tofts C, Avis T, Barthorpe S, Buck G, Cole J, Gray K, Halliday K, Harrison R, Hills K, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Varian J, West S, Widaa S, Mallya U, Moon J, Luo Y, Holder S, Smithson SF, Hurst JA, Clayton-Smith J, Kerr B, Boyle J, Shaw M, Vandeleur L, Rodriguez J, Slaugh R, Easton DF, Wooster R, Bobrow M, Srivastava AK, Stevenson RE, Schwartz CE, Turner G, Gecz J, Futreal PA, Stratton MR, Partington M (Feb 2007). "Mutations in CUL4B, which encodes a ubiquitin E3 ligase subunit, cause an X-linked mental retardation syndrome associated with aggressive outbursts, seizures, relative macrocephaly, central obesity, hypogonadism, pes cavus, and tremor". American Journal of Human Genetics. 80 (2): 345–52. doi:10.1086/511134. PMID 17236139. 
  16. ^ Vulto-van Silfhout AT, Nakagawa T, Bahi-Buisson N, Haas SA, Hu H, Bienek M, Vissers LE, Gilissen C, Tzschach A, Busche A, Müsebeck J, Rump P, Mathijssen IB, Avela K, Somer M, Doagu F, Philips AK, Rauch A, Baumer A, Voesenek K, Poirier K, Vigneron J, Amram D, Odent S, Nawara M, Obersztyn E, Lenart J, Charzewska A, Lebrun N, Fischer U, Nillesen WM, Yntema HG, Järvelä I, Ropers HH, de Vries BB, Brunner HG, van Bokhoven H, Raymond FL, Willemsen MA, Chelly J, Xiong Y, Barkovich AJ, Kalscheuer VM, Kleefstra T, de Brouwer AP (Jan 2015). "Variants in CUL4B are associated with cerebral malformations". Human Mutation. 36 (1): 106–17. doi:10.1002/humu.22718. PMID 25385192. 
  17. ^ a b c Sharifi HJ, Furuya AK, Jellinger RM, Nekorchuk MD, de Noronha CM (Jun 2014). "Cullin4A and cullin4B are interchangeable for HIV Vpr and Vpx action through the CRL4 ubiquitin ligase complex". Journal of Virology. 88 (12): 6944–58. doi:10.1128/JVI.00241-14. PMID 24719410. 
  18. ^ Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H (Mar 2010). "Identification of a primary target of thalidomide teratogenicity". Science. 327 (5971): 1345––50. doi:10.1126/science.1177319. PMID 20223979. 
  19. ^ a b c Lu G, Middleton RE, Sun H, Naniong M, Ott CJ, Mitsiades CS, Wong KK, Bradner JE, Kaelin WG (Jan 2014). "The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins". Science. 343 (6168): 305–9. doi:10.1126/science.1244917. PMID 24292623. 
  20. ^ a b c Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL (Jan 2014). "Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells". Science. 343 (6168): 301–5. doi:10.1126/science.1244851. PMC 4077049Freely accessible. PMID 24292625. 
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  22. ^ Min KW, Hwang JW, Lee JS, Park Y, Tamura TA, Yoon JB (May 2003). "TIP120A associates with cullins and modulates ubiquitin ligase activity". J. Biol. Chem. 278 (18): 15905–10. doi:10.1074/jbc.M213070200. PMID 12609982. 
  23. ^ Guerrero-Santoro J, Kapetanaki MG, Hsieh CL, Gorbachinsky I, Levine AS, Rapić-Otrin V (Jul 2008). "The cullin 4B-based UV-damaged DNA-binding protein ligase binds to UV-damaged chromatin and ubiquitinates histone H2A". Cancer Research. 68 (13): 5014–22. doi:10.1158/0008-5472.CAN-07-6162. PMID 18593899. 
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Further reading[edit]