CBX5 (gene)

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CBX5
Protein CBX5 PDB 3FDT.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases CBX5, HEL25, HP1, HP1A, chromobox 5
External IDs MGI: 109372 HomoloGene: 7257 GeneCards: CBX5
RNA expression pattern
PBB GE CBX5 209715 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_012117
NM_001127321
NM_001127322

NM_001076789
NM_001110216
NM_007626

RefSeq (protein)

NP_001120793
NP_001120794
NP_036249

Location (UCSC) Chr 12: 54.23 – 54.28 Mb Chr 15: 103.19 – 103.24 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene.[3][4] It is a highly conserved, non-histone protein part of the heterochromatin family. The protein itself is more commonly called (in humans) HP1α.[citation needed] Heterochromatin protein-1 (HP1) has an N-terminal domain that acts on methylated lysines residues leading to epigenetic repression.[5] 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.[6]

Structure[edit]

HP1α is 191 amino acids in length containing 6 exons.[5][6] 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.[6] Connecting these two domains is the hinge region.[7]

Chromodomain[edit]

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.[7] 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.[6] 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.[7]

Chromoshadow Domain[edit]

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.[7] 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.[6]

Mechanism of Action[edit]

HP1α primarily functions as a gene silencer, which is dependent on the interactions between the CD and the methyl H3K9 mark.[8] 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.[7] 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.[7]

Evolutionary Conservation[edit]

HP1α is a highly evolutionary conserved protein, existing in species such a Schizosaccharomyces pombe, a type of yeast, all the way to humans.[7] 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).[7]

Interactions[edit]

CBX5 (gene) has been shown to interact with:

See also[edit]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ Ye Q, Worman HJ (Jun 1996). "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. doi:10.1074/jbc.271.25.14653. PMID 8663349. 
  4. ^ "Entrez Gene: CBX5 chromobox homolog 5 (HP1 alpha homolog, Drosophila)". 
  5. ^ a b "OMIM Entry- * 604478 - CHROMOBOX HOMOLOG 5; CBX5". omim.org. Retrieved 2015-11-02. 
  6. ^ a b c d e Lomberk G, Wallrath L, Urrutia R (2006). "The heterochromatin protein 1 family". Genome Biol. 7 (7): 228. doi:10.1186/gb-2006-7-7-228. PMC 1779566Freely accessible. PMID 17224041. 
  7. ^ a b c d e f g h Hiragami, K (15 August 2005). "Heterochromatin Protein 1: a pervasive controlling influence". Cellular and Molecular Life Sciences. 62: 2711–2726. doi:10.1007/s00018-005-5287-9. PMID 16261261. Retrieved 30 Oct 2015. 
  8. ^ "CBX5 chromobox homolog 5 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2015-10-16. 
  9. ^ a b c Nielsen AL, Oulad-Abdelghani M, Ortiz JA, Remboutsika E, Chambon P, Losson R (Apr 2001). "Heterochromatin formation in mammalian cells: interaction between histones and HP1 proteins". Molecular Cell. 7 (4): 729–39. doi:10.1016/S1097-2765(01)00218-0. PMID 11336697. 
  10. ^ a b Reese BE, Bachman KE, Baylin SB, Rountree MR (May 2003). "The methyl-CpG binding protein MBD1 interacts with the p150 subunit of chromatin assembly factor 1". Molecular and Cellular Biology. 23 (9): 3226–36. doi:10.1128/mcb.23.9.3226-3236.2003. PMC 153189Freely accessible. PMID 12697822. 
  11. ^ a b Lechner MS, Begg GE, Speicher DW, Rauscher FJ (Sep 2000). "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. doi:10.1128/mcb.20.17.6449-6465.2000. PMC 86120Freely accessible. PMID 10938122. 
  12. ^ Lehnertz B, Ueda Y, Derijck AA, Braunschweig U, Perez-Burgos L, Kubicek S, Chen T, Li E, Jenuwein T, Peters AH (Jul 2003). "Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin". Current Biology. 13 (14): 1192–200. doi:10.1016/s0960-9822(03)00432-9. PMID 12867029. 
  13. ^ a b c d Zhang CL, McKinsey TA, Olson EN (Oct 2002). "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. doi:10.1128/mcb.22.20.7302-7312.2002. PMC 139799Freely accessible. PMID 12242305. 
  14. ^ Song K, Jung Y, Jung D, Lee I (Mar 2001). "Human Ku70 interacts with heterochromatin protein 1alpha". The Journal of Biological Chemistry. 276 (11): 8321–7. doi:10.1074/jbc.M008779200. PMID 11112778. 
  15. ^ Ye Q, Worman HJ (Jun 1996). "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. doi:10.1074/jbc.271.25.14653. PMID 8663349. 
  16. ^ a b Fujita N, Watanabe S, Ichimura T, Tsuruzoe S, Shinkai Y, Tachibana M, Chiba T, Nakao M (Jun 2003). "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. doi:10.1074/jbc.M302283200. PMID 12711603. 
  17. ^ Obuse C, Iwasaki O, Kiyomitsu T, Goshima G, Toyoda Y, Yanagida M (Nov 2004). "A conserved Mis12 centromere complex is linked to heterochromatic HP1 and outer kinetochore protein Zwint-1". Nature Cell Biology. 6 (11): 1135–41. doi:10.1038/ncb1187. PMID 15502821. 
  18. ^ a b Nielsen AL, Sanchez C, Ichinose H, Cerviño M, Lerouge T, Chambon P, Losson R (Nov 2002). "Selective interaction between the chromatin-remodeling factor BRG1 and the heterochromatin-associated protein HP1alpha". The EMBO Journal. 21 (21): 5797–806. doi:10.1093/emboj/cdf560. PMC 131057Freely accessible. PMID 12411497. 
  19. ^ 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 (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. 
  20. ^ Vassallo MF, Tanese N (Apr 2002). "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. doi:10.1073/pnas.092025499. PMC 122877Freely accessible. PMID 11959914. 
  21. ^ Cammas F, Oulad-Abdelghani M, Vonesch JL, Huss-Garcia Y, Chambon P, Losson R (Sep 2002). "Cell differentiation induces TIF1beta association with centromeric heterochromatin via an HP1 interaction". Journal of Cell Science. 115 (Pt 17): 3439–48. PMID 12154074. 
  22. ^ Hu X, Dutta P, Tsurumi A, Li J, Wang J, Land H, Li WX (Jun 2013). "Unphosphorylated STAT5A stabilizes heterochromatin and suppresses tumor growth". Proc Natl Acad Sci U S A. 110 (25): 10213–10218. doi:10.1073/pnas.1221243110. PMC 3690839Freely accessible. PMID 23733954. 

External links[edit]

Further reading[edit]