CBX5 (gene)

Chromobox protein homolog 5 is a protein that in humans is encoded by the CBX5 gene. 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.

CBX5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3FDT, 3I3C
Identifiers
Aliases	CBX5, HEL25, HP1, HP1A, chromobox 5
External IDs	OMIM: 604478; MGI: 109372; HomoloGene: 7257; GeneCards: CBX5; OMA:CBX5 - orthologs
Gene location (Human) Chr. Chromosome 12 (human) Band 12q13.13 Start 54,230,942 bp End 54,280,133 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15|15 F3 Start 103,099,971 bp End 103,148,243 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tendon of biceps brachii caput epididymis corpus epididymis internal globus pallidus tail of epididymis retinal pigment epithelium ventricular zone mucosa of paranasal sinus ganglionic eminence entorhinal cortex Top expressed in tail of embryo maxillary prominence mandibular prominence genital tubercle somite hand epiblast abdominal wall ventricular zone Gonadal ridge More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein homodimerization activity protein binding protein-macromolecule adaptor activity chromatin binding histone deacetylase binding methylated histone binding ribonucleoprotein complex binding protein-containing complex binding identical protein binding Cellular component kinetochore nucleus nuclear envelope pericentric heterochromatin nucleolus histone deacetylase complex nucleoplasm chromocenter heterochromatin chromosome, centromeric region histone methyltransferase complex transcription repressor complex chromosome PML body protein-containing complex ribonucleoprotein complex site of DNA damage Biological process blood coagulation negative regulation of transcription, DNA-templated viral process negative regulation of transcription by RNA polymerase II negative regulation of G0 to G1 transition cellular response to DNA damage stimulus Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 23468 12419 Ensembl ENSG00000094916 ENSMUSG00000009575 UniProt P45973 Q61686 RefSeq (mRNA) NM_012117 NM_001127321 NM_001127322 NM_001076789 NM_001110216 NM_007626 NM_001358950 RefSeq (protein) NP_001120793 NP_001120794 NP_036249 NP_001070257 NP_001103686 NP_031652 NP_001345879 Location (UCSC) Chr 12: 54.23 – 54.28 Mb Chr 15: 103.1 – 103.15 Mb PubMed search
Wikidata
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Structure

HP1α is 191 amino acids in length containing 6 exons. 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.

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. 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:

• CBX1,
• CBX3,
• CHAF1A,
• DNMT3B,
• HDAC4,
• HDAC9,
• Histone deacetylase 5,
• Ku70,
• Lamin B receptor,
• MBD1,
• MIS12,
• SMARCA4,
• SUV39H1,
• TAF4, and
• TRIM28.
• STAT5A,

See also

• Heterochromatin protein 1

Further reading

• Saunders WS, Chue C, Goebl M, Craig C, Clark RF, Powers JA, Eissenberg JC, Elgin SC, Rothfield NF, Earnshaw WC (Feb 1993). "Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity". Journal of Cell Science. 104 (2): 573–82. doi:10.1242/jcs.104.2.573. PMID 8505380.
• Sugimoto K, Yamada T, Muro Y, Himeno M (Jul 1996). "Human homolog of Drosophila heterochromatin-associated protein 1 (HP1) is a DNA-binding protein which possesses a DNA-binding motif with weak similarity to that of human centromere protein C (CENP-C)". Journal of Biochemistry. 120 (1): 153–9. doi:10.1093/oxfordjournals.jbchem.a021378. PMID 8864858.
• Ye Q, Callebaut I, Pezhman A, Courvalin JC, Worman HJ (Jun 1997). "Domain-specific interactions of human HP1-type chromodomain proteins and inner nuclear membrane protein LBR". The Journal of Biological Chemistry. 272 (23): 14983–9. doi:10.1074/jbc.272.23.14983. PMID 9169472. S2CID 39872511.
• Lessard J, Baban S, Sauvageau G (Feb 1998). "Stage-specific expression of polycomb group genes in human bone marrow cells". Blood. 91 (4): 1216–24. doi:10.1182/blood.V91.4.1216. PMID 9454751.
• Ainsztein AM, Kandels-Lewis SE, Mackay AM, Earnshaw WC (Dec 1998). "INCENP centromere and spindle targeting: identification of essential conserved motifs and involvement of heterochromatin protein HP1". The Journal of Cell Biology. 143 (7): 1763–74. doi:10.1083/jcb.143.7.1763. PMC 2175214. PMID 9864353.
• Minc E, Allory Y, Worman HJ, Courvalin JC, Buendia B (Aug 1999). "Localization and phosphorylation of HP1 proteins during the cell cycle in mammalian cells". Chromosoma. 108 (4): 220–34. doi:10.1007/s004120050372. PMID 10460410. S2CID 12381860.
• Murzina N, Verreault A, Laue E, Stillman B (Oct 1999). "Heterochromatin dynamics in mouse cells: interaction between chromatin assembly factor 1 and HP1 proteins". Molecular Cell. 4 (4): 529–40. doi:10.1016/S1097-2765(00)80204-X. PMID 10549285.
• Nielsen AL, Ortiz JA, You J, Oulad-Abdelghani M, Khechumian R, Gansmuller A, Chambon P, Losson R (Nov 1999). "Interaction with members of the heterochromatin protein 1 (HP1) family and histone deacetylation are differentially involved in transcriptional silencing by members of the TIF1 family". The EMBO Journal. 18 (22): 6385–95. doi:10.1093/emboj/18.22.6385. PMC 1171701. PMID 10562550.
• Zhao T, Heyduk T, Allis CD, Eissenberg JC (Sep 2000). "Heterochromatin protein 1 binds to nucleosomes and DNA in vitro". The Journal of Biological Chemistry. 275 (36): 28332–8. doi:10.1074/jbc.M003493200. PMID 10882726.
• 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 86120. PMID 10938122.
• 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. S2CID 84712852.
• Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T (Mar 2001). "Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins". Nature. 410 (6824): 116–20. doi:10.1038/35065132. PMID 11242053. S2CID 4331863.
• Bannister AJ, Zegerman P, Partridge JF, Miska EA, Thomas JO, Allshire RC, Kouzarides T (Mar 2001). "Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain". Nature. 410 (6824): 120–4. doi:10.1038/35065138. PMID 11242054. S2CID 4334447.
• 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. hdl:10261/308369. PMID 11336697.
• Wheatley SP, Carvalho A, Vagnarelli P, Earnshaw WC (Jun 2001). "INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis". Current Biology. 11 (11): 886–90. Bibcode:2001CBio...11..886W. doi:10.1016/S0960-9822(01)00238-X. PMID 11516652. S2CID 381637.
• Scholzen T, Endl E, Wohlenberg C, van der Sar S, Cowell IG, Gerdes J, Singh PB (Feb 2002). "The Ki-67 protein interacts with members of the heterochromatin protein 1 (HP1) family: a potential role in the regulation of higher-order chromatin structure". The Journal of Pathology. 196 (2): 135–44. doi:10.1002/path.1016. PMID 11793364. S2CID 36130549.
• Weinmann AS, Yan PS, Oberley MJ, Huang TH, Farnham PJ (Jan 2002). "Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis". Genes & Development. 16 (2): 235–44. doi:10.1101/gad.943102. PMC 155318. PMID 11799066.
• Sugimoto K, Tasaka H, Dotsu M (Dec 2001). "Molecular behavior in living mitotic cells of human centromere heterochromatin protein HPLalpha ectopically expressed as a fusion to red fluorescent protein". Cell Structure and Function. 26 (6): 705–18. doi:10.1247/csf.26.705. PMID 11942629.
• 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. Bibcode:2002PNAS...99.5919V. doi:10.1073/pnas.092025499. PMC 122877. PMID 11959914.

External links

• Human CBX5 genome location and CBX5 gene details page in the UCSC Genome Browser.