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Cat Eye Syndrome Chromosome Region Candidate 2

Function

The Cat Eye Syndrome Chromosome Region Candidate 2 (CECR2) is the regulatory subunit of the ATP-dependent CERF-1 and CERF-5 ISWI chromatin remodeling complexes that modulate nucleosome spacing and DNA accessibility during replication and transcription.^[1]^[2]^[3]^[4]. CECR2 also plays a key role in the DNA damage repair response, as it inhibits γ-H2AX activity.^[5]. CECR2 is involved in various processes during development, including embryogenesis and spermatogenesis.^[6]^[7]. Recent studies have identified CECR2 as an epigenetic regulator of NF-kB pro-inflammatory gene expression through the recognition of acetylated RelA and driving breast cancer metastasis.^[8]

Domain Organization

The full-length CECR2 is composed of an N-terminus DDT domain (DNA-binding homeobox and different transcription factors), an AT-hook, and a bromodomain.^[9]^[10]The DDT and the AT-hook domain bind DNA, while the bromodomain recognizes acetylated lysine.^[11]^[12]^[13]

Sequential and Structural Conservation

100% match, indicative of its importance

It is also structurally conserved, function, mechanism is important

Bromodomains

Acetyllysine on histones (how and what)

Meaning, bromodomain function

Bromodomains are composed of 4 alpha helices (αZ, αA, αB, αC), and 2 loops (ZA and BC). There are typically 4 conserved water molecules found within the acetyllysine binding pocket of the bromodomain. The two loops contain the majority of the residues responsible for ligand coordination, including the conserved asparagine located in the BC loop. In addition, there is a hydrophobic shelf found before the before the ZA loop and following αZ helix. There is also a gatekeeper residue that corresponds to the first residue found in the αC that is usually hydrophobic. Histone acetyllysines form a hydrogen bond with the conserved asparagine of bromodomains while various other residues make polar contacts to stabilize the interaction, directly or indirectly.^[14]

While there is no solved structure for histone bound, we can assume (ref)

Disease and Therapeutics

Diseases found

inhibition with small molecule

These contacts in CECR2. N514, D464, Y520 (no contact) ^[15] conserved asparagine

Cpd6 inhibitor N514 2 bonds

↑ Banting GS, Barak O, Ames TM, Burnham AC, Kardel MD, Cooch NS, Davidson CE, Godbout R, McDermid HE, Shiekhattar R. CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Hum Mol Genet. 2005 Feb 15;14(4):513-24. Epub 2005 Jan 7. PMID:15640247 doi:https://dx.doi.org/ddi048
↑ Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013
↑ Flynn EM, Huang OW, Poy F, Oppikofer M, Bellon SF, Tang Y, Cochran AG. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure. 2015 Sep 4. pii: S0969-2126(15)00329-9. doi:, 10.1016/j.str.2015.08.004. PMID:26365797 doi:https://dx.doi.org/10.1016/j.str.2015.08.004
↑ Oppikofer M, Bai T, Gan Y, Haley B, Liu P, Sandoval W, Ciferri C, Cochran AG. Expansion of the ISWI chromatin remodeler family with new active complexes. EMBO Rep. 2017 Oct;18(10):1697-1706. PMID:28801535 doi:10.15252/embr.201744011
↑ Lee SK, Park EJ, Lee HS, Lee YS, Kwon J. Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein. Mol Cells. 2012 Jul;34(1):85-91. PMID:22699752 doi:10.1007/s10059-012-0112-4
↑ Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013
↑ Flynn EM, Huang OW, Poy F, Oppikofer M, Bellon SF, Tang Y, Cochran AG. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure. 2015 Sep 4. pii: S0969-2126(15)00329-9. doi:, 10.1016/j.str.2015.08.004. PMID:26365797 doi:https://dx.doi.org/10.1016/j.str.2015.08.004
↑ Zhang M, Liu ZZ, Aoshima K, Cai WL, Sun H, Xu T, Zhang Y, An Y, Chen JF, Chan LH, Aoshima A, Lang SM, Tang Z, Che X, Li Y, Rutter SJ, Bossuyt V, Chen X, Morrow JS, Pusztai L, Rimm DL, Yin M, Yan Q. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Sci Transl Med. 2022 Feb 2;14(630):eabf5473. PMID:35108062 doi:10.1126/scitranslmed.abf5473
↑ Wu L, Zhao G, Xu S, Kuang J, Ming J, Wu G, Wang T, Wang B, Zhu P, Pei D, Liu J. The nuclear factor CECR2 promotes somatic cell reprogramming by reorganizing the chromatin structure. J Biol Chem. 2021 Jan-Jun;296:100022. doi: 10.1074/jbc.RA120.014598. Epub 2020 , Nov 23. PMID:33144328 doi:https://dx.doi.org/10.1074/jbc.RA120.014598
↑ doi: https://dx.doi.org/10.1387/ijdb.092933jc
↑ doi: https://dx.doi.org/10.1093/nar/26.19.4413.
↑ doi: https://dx.doi.org/10.1111/jipb.12069FromNLMMedline.
↑ Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013
↑ Meslamani J, Smith SG, Sanchez R, Zhou MM. Structural features and inhibitors of bromodomains. Drug Discov Today Technol. 2016 Mar;19:3-15. PMID:27769355 doi:10.1016/j.ddtec.2016.09.001
↑ Crawford TD, Audia JE, Bellon S, Burdick DJ, Bommi-Reddy A, Cote A, Cummings RT, Duplessis M, Flynn EM, Hewitt M, Huang HR, Jayaram H, Jiang Y, Joshi S, Kiefer JR, Murray J, Nasveschuk CG, Neiss A, Pardo E, Romero FA, Sandy P, Sims RJ 3rd, Tang Y, Taylor AM, Tsui V, Wang J, Wang S, Wang Y, Xu Z, Zawadzke L, Zhu X, Albrecht BK, Magnuson SR, Cochran AG. GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2). ACS Med Chem Lett. 2017 Jun 1;8(7):737-741. doi: 10.1021/acsmedchemlett.7b00132. , eCollection 2017 Jul 13. PMID:28740608 doi:https://dx.doi.org/10.1021/acsmedchemlett.7b00132

References

Proteopedia Page Contributors and Editors (what is this?)

Elizabeth Cook

[1] Banting GS, Barak O, Ames TM, Burnham AC, Kardel MD, Cooch NS, Davidson CE, Godbout R, McDermid HE, Shiekhattar R. CECR2, a protein involved in neurulation, forms a novel chromatin remodeling complex with SNF2L. Hum Mol Genet. 2005 Feb 15;14(4):513-24. Epub 2005 Jan 7. PMID:15640247 doi:https://dx.doi.org/ddi048

[2] Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013

[3] Flynn EM, Huang OW, Poy F, Oppikofer M, Bellon SF, Tang Y, Cochran AG. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure. 2015 Sep 4. pii: S0969-2126(15)00329-9. doi:, 10.1016/j.str.2015.08.004. PMID:26365797 doi:https://dx.doi.org/10.1016/j.str.2015.08.004

[4] Oppikofer M, Bai T, Gan Y, Haley B, Liu P, Sandoval W, Ciferri C, Cochran AG. Expansion of the ISWI chromatin remodeler family with new active complexes. EMBO Rep. 2017 Oct;18(10):1697-1706. PMID:28801535 doi:10.15252/embr.201744011

[5] Lee SK, Park EJ, Lee HS, Lee YS, Kwon J. Genome-wide screen of human bromodomain-containing proteins identifies Cecr2 as a novel DNA damage response protein. Mol Cells. 2012 Jul;34(1):85-91. PMID:22699752 doi:10.1007/s10059-012-0112-4

[6] Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013

[7] Flynn EM, Huang OW, Poy F, Oppikofer M, Bellon SF, Tang Y, Cochran AG. A Subset of Human Bromodomains Recognizes Butyryllysine and Crotonyllysine Histone Peptide Modifications. Structure. 2015 Sep 4. pii: S0969-2126(15)00329-9. doi:, 10.1016/j.str.2015.08.004. PMID:26365797 doi:https://dx.doi.org/10.1016/j.str.2015.08.004

[8] Zhang M, Liu ZZ, Aoshima K, Cai WL, Sun H, Xu T, Zhang Y, An Y, Chen JF, Chan LH, Aoshima A, Lang SM, Tang Z, Che X, Li Y, Rutter SJ, Bossuyt V, Chen X, Morrow JS, Pusztai L, Rimm DL, Yin M, Yan Q. CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Sci Transl Med. 2022 Feb 2;14(630):eabf5473. PMID:35108062 doi:10.1126/scitranslmed.abf5473

[9] Wu L, Zhao G, Xu S, Kuang J, Ming J, Wu G, Wang T, Wang B, Zhu P, Pei D, Liu J. The nuclear factor CECR2 promotes somatic cell reprogramming by reorganizing the chromatin structure. J Biol Chem. 2021 Jan-Jun;296:100022. doi: 10.1074/jbc.RA120.014598. Epub 2020 , Nov 23. PMID:33144328 doi:https://dx.doi.org/10.1074/jbc.RA120.014598

[10] : https://dx.doi.org/10.1387/ijdb.092933jc

[11] : https://dx.doi.org/10.1093/nar/26.19.4413.

[12] : https://dx.doi.org/10.1111/jipb.12069FromNLMMedline.

[13] Filippakopoulos P, Picaud S, Mangos M, Keates T, Lambert JP, Barsyte-Lovejoy D, Felletar I, Volkmer R, Muller S, Pawson T, Gingras AC, Arrowsmith CH, Knapp S. Histone recognition and large-scale structural analysis of the human bromodomain family. Cell. 2012 Mar 30;149(1):214-31. PMID:22464331 doi:10.1016/j.cell.2012.02.013

[14] Meslamani J, Smith SG, Sanchez R, Zhou MM. Structural features and inhibitors of bromodomains. Drug Discov Today Technol. 2016 Mar;19:3-15. PMID:27769355 doi:10.1016/j.ddtec.2016.09.001

[15] Crawford TD, Audia JE, Bellon S, Burdick DJ, Bommi-Reddy A, Cote A, Cummings RT, Duplessis M, Flynn EM, Hewitt M, Huang HR, Jayaram H, Jiang Y, Joshi S, Kiefer JR, Murray J, Nasveschuk CG, Neiss A, Pardo E, Romero FA, Sandy P, Sims RJ 3rd, Tang Y, Taylor AM, Tsui V, Wang J, Wang S, Wang Y, Xu Z, Zawadzke L, Zhu X, Albrecht BK, Magnuson SR, Cochran AG. GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2). ACS Med Chem Lett. 2017 Jun 1;8(7):737-741. doi: 10.1021/acsmedchemlett.7b00132. , eCollection 2017 Jul 13. PMID:28740608 doi:https://dx.doi.org/10.1021/acsmedchemlett.7b00132

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@@ Line 15: / Line 15: @@
 == Sequential and Structural Conservation ==
-[[Image:Msa.jpg |500px|]][[Image:Conserved_cecr2.jpg |500px|]]
+[[Image:Msa.jpg |500px|]]
+% match, indicative of its importance
+[[Image:Conserved_cecr2.jpg |500px|]]
+It is also structurally conserved, function, mechanism is important
 == Bromodomains ==
+Acetyllysine on histones (how and what)
+Meaning, bromodomain function
 Bromodomains are composed of 4 alpha helices (<scene name='10/1079536/Helix/1'>αZ, αA, αB, αC)</scene>, and 2 loops (ZA and BC). There are typically 4 conserved water molecules found within the acetyllysine binding pocket of the bromodomain. The two loops contain the majority of the residues responsible for ligand coordination, including the <scene name='10/1079536/N514_part_2/1'>conserved asparagine</scene> located in the BC loop. In addition, there is a hydrophobic shelf found before the before the ZA loop and following αZ helix. There is also a <scene name='10/1079536/Gatekeeper/1'>gatekeeper residue</scene> that corresponds to the first residue found in the αC that is usually hydrophobic. Histone acetyllysines form a hydrogen bond with the conserved asparagine of bromodomains while various other residues make polar contacts to stabilize the interaction, directly or indirectly.<ref>PMID:27769355</ref>
+While there is no solved structure for histone bound, we can assume (ref)
 == Disease and Therapeutics ==
+Diseases found
+inhibition with small molecule
 [[Image:Cecr2_contacts.png|center|400px|]]
@@ Line 29: / Line 45: @@
 <scene name='10/1079536/Cpd6/1'>Cpd6 inhibitor</scene> <scene name='10/1079536/N514/1'>N514</scene> <scene name='10/1079536/2_bonds/1'>2 bonds</scene>
 </StructureSection>
 == References ==
 <references/>

User:Elizabeth Cook/Sandbox 1: Difference between revisions

Revision as of 05:28, 29 April 2025

Cat Eye Syndrome Chromosome Region Candidate 2

Contents

Function

Domain Organization

Sequential and Structural Conservation

Bromodomains

Disease and Therapeutics

References

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