CBX5 (gene) explained

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene.[1] [2] It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called (in humans) HP1α. Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression. The C-terminal of this protein has a chromo shadow-domain (CSD) that is responsible for homodimerizing, as well as interacting with a variety of chromatin-associated, non-histone proteins.

Structure

HP1α is 191 amino acids in length containing 6 exons.[3] [4] As mentioned above, this protein contains two domains, an N-terminal chromodomain (CD) and a C- terminal chromoshadow domain (CSD). The CD binds with histone 3 through a methylated lysine residue at position 9 (H3K9) while the C-terminal CSD homodimerizes and interacts with a variety of other chromatin-associated, non-histone related proteins. Connecting these two domains is the hinge region.[5]

Chromodomain

Once translated, the chromodomain will take on a globular conformation consisting of three β-sheets and one α-helix. The β-sheets are packed up against the helix at the carboxy terminal segment. The charges on the β sheets are negative thus making it difficult for it to bind to the DNA as a DNA-binding motif. Instead, HP1α binds to the histones as a protein interaction motif. Specific binding to CD to the methylated H3K9 is mediated by three hydrophobic side chains called the "hydrophobic box". Other sites on HP1 will interact with the H3 tails from neighbouring histones which will give structure to the flexible N-terminal tail of the histones. Neighbouring H3 histones can affect HP1 binding by post-translationally modifying the tails.

Chromoshadow domain

The CSD much resembles that of the CD. It too has a globular conformation containing three β-sheets, however it possesses two α-helices as opposed to just the one in the CD. The CSD readily homodimerizes in vitro and as a result forms a groove which can accommodate HP1 associated proteins that have a specific consensus sequence: PxVxL, where P is Proline, V is Valine, L is Leucine and x is any amino acid.

Mechanism of action

HP1α primarily functions as a gene silencer, which is dependent on the interactions between the CD and the methyl H3K9 mark.[6] The hydrophobic box on the CD provides the appropriate environment for the methylated lysine residue. While the exact mechanism of how gene silencing is done is unknown, experimental data concluded the rapid exchange of biological macromolecules in and out of the heterochromatin region. This suggests HP1 isn't acting as a glue holding the heterochromatin together, but rather there are competing molecules within that interact in various ways to create a closed complex leading to gene repression or an open, euchromatin structure with gene activation. HP1 concentration is higher and more static in areas of the chromosome where methylated H3K9 residues reside, giving the chromosome its closed, gene-repressed heterochromatin structure. It has also been shown that the more methylated the H3 lysine is, the higher the affinity HP1 has for it. That is, trimethylated lysine residues bind tighter to HP1 than dimethylated residues, which bind better than monomethylated residues.

The localisation driving factor is currently unknown.

Evolutionary conservation

HP1α is a highly evolutionarily conserved protein, existing in species such as Schizosaccharomyces pombe, a type of yeast, all the way to humans. The N-terminal chromodomain and C-terminal chromoshadow domain appear to be much more conserved (approximately 50-70% amino acid similarity) than the hinge region (approximately 25-30% similarity with the Drosophila HP1 homolog).

Interactions

CBX5 (gene) has been shown to interact with:

See also

Further reading

Notes and References

  1. Ye Q, Worman HJ . Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1 . The Journal of Biological Chemistry . 271 . 25 . 14653–6 . Jun 1996 . 8663349 . 10.1074/jbc.271.25.14653 . 23643628 . free .
  2. Web site: Entrez Gene: CBX5 chromobox homolog 5 (HP1 alpha homolog, Drosophila).
  3. Web site: OMIM Entry- * 604478 - CHROMOBOX HOMOLOG 5; CBX5. omim.org. 2015-11-02.
  4. Lomberk G, Wallrath L, Urrutia R . 2006 . The heterochromatin protein 1 family . Genome Biol . 7 . 7. 228 . 10.1186/gb-2006-7-7-228 . 17224041 . 1779566 . free .
  5. Heterochromatin Protein 1: a pervasive controlling influence. Hiragami. K. 15 August 2005. Cellular and Molecular Life Sciences. 10.1007/s00018-005-5287-9. 16261261. 62. 23. 2711–2726. 31117054. 11139183.
  6. Web site: CBX5 chromobox homolog 5 [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2015-10-16.
  7. Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH . Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin . Current Biology . 13 . 14 . 1192–200 . Jul 2003 . 12867029 . 10.1016/s0960-9822(03)00432-9. 2320997 . free . 2003CBio...13.1192L .
  8. Zhang CL, McKinsey TA, Olson EN . Association of class II histone deacetylases with heterochromatin protein 1: potential role for histone methylation in control of muscle differentiation . Molecular and Cellular Biology . 22 . 20 . 7302–12 . Oct 2002 . 12242305 . 139799 . 10.1128/mcb.22.20.7302-7312.2002.
  9. Song K, Jung Y, Jung D, Lee I . Human Ku70 interacts with heterochromatin protein 1alpha . The Journal of Biological Chemistry . 276 . 11 . 8321–7 . Mar 2001 . 11112778 . 10.1074/jbc.M008779200 . 84712852 . free .
  10. Ye Q, Worman HJ . Interaction between an integral protein of the nuclear envelope inner membrane and human chromodomain proteins homologous to Drosophila HP1 . The Journal of Biological Chemistry . 271 . 25 . 14653–6 . Jun 1996 . 8663349 . 10.1074/jbc.271.25.14653. 23643628 . free .
  11. Reese BE, Bachman KE, Baylin SB, Rountree MR . The methyl-CpG binding protein MBD1 interacts with the p150 subunit of chromatin assembly factor 1 . Molecular and Cellular Biology . 23 . 9 . 3226–36 . May 2003 . 12697822 . 153189 . 10.1128/mcb.23.9.3226-3236.2003.
  12. Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M . Methyl-CpG binding domain 1 (MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNA methylation-based transcriptional repression . The Journal of Biological Chemistry . 278 . 26 . 24132–8 . Jun 2003 . 12711603 . 10.1074/jbc.M302283200 . 24340120 . free .
  13. Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M . A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1 . Nature Cell Biology . 6 . 11 . 1135–41 . Nov 2004 . 15502821 . 10.1038/ncb1187 . 39408000 .
  14. Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M . Towards a proteome-scale map of the human protein-protein interaction network . Nature . 437 . 7062 . 1173–8 . Oct 2005 . 16189514 . 10.1038/nature04209 . 2005Natur.437.1173R . 4427026 .
  15. Vassallo MF, Tanese N . Isoform-specific interaction of HP1 with human TAFII130 . Proceedings of the National Academy of Sciences of the United States of America . 99 . 9 . 5919–24 . Apr 2002 . 11959914 . 122877 . 10.1073/pnas.092025499 . 2002PNAS...99.5919V . free .
  16. Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R . Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins . Molecular Cell . 7 . 4 . 729–39 . Apr 2001 . 11336697 . 10.1016/S1097-2765(01)00218-0. free . 10261/308369 . free .
  17. Lechner MS, Begg GE, Speicher DW, Rauscher FJ . Molecular determinants for targeting heterochromatin protein 1-mediated gene silencing: direct chromoshadow domain-KAP-1 corepressor interaction is essential . Molecular and Cellular Biology . 20 . 17 . 6449–65 . Sep 2000 . 10938122 . 86120 . 10.1128/mcb.20.17.6449-6465.2000.
  18. Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R . Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha . The EMBO Journal . 21 . 21 . 5797–806 . Nov 2002 . 12411497 . 131057 . 10.1093/emboj/cdf560.
  19. Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R . Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction . Journal of Cell Science . 115 . Pt 17 . 3439–48 . Sep 2002 . 10.1242/jcs.115.17.3439 . 12154074 . free .
  20. Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, Li WX . Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth . Proc Natl Acad Sci U S A . 110 . 25 . 10213–10218 . Jun 2013 . 23733954 . 10.1073/pnas.1221243110 . 3690839. 2013PNAS..11010213H . free .