9b4p

Tetramer Formation of the BCL11A ZF0 Domain

Structural highlights

9b4p is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.56Å
Ligands:	ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

BC11A_HUMAN Hereditary persistence of fetal hemoglobin - beta-thalassemia. Chromosomal aberrations involving BCL11A may be a cause of lymphoid malignancies. Translocation t(2;14)(p13;q32.3) causes BCL11A deregulation and amplification.^[1] The disease is caused by mutations affecting the gene represented in this entry.^[2]

Function

BC11A_HUMAN Transcription factor associated with the BAF SWI/SNF chromatin remodeling complex (By similarity). Repressor of fetal hemoglobin (HbF) level (PubMed:26375765). Involved in brain development (PubMed:27453576). Functions as a myeloid and B-cell proto-oncogene. May play important roles in leukemogenesis and hematopoiesis. Essential factor in lymphopoiesis required for B-cell formation in fetal liver. May function as a modulator of the transcriptional repression activity of ARP1 (By similarity).[UniProtKB:Q9QYE3]^[3] ^[4]

Publication Abstract from PubMed

Down-regulation of BCL11A protein reverses the fetal (HbF, alpha(2)gamma(2)) to adult (HbA, alpha(2)beta(2)) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells. We report that tetramer formation mediated by a single zinc finger (ZnF0) is required for production of steady-state protein. Beyond its role in protein stability, the tetramer state is necessary for gamma-globin gene repression, because an engineered monomer fails to engage a critical co-repressor complex. These aspects of BCL11A protein production identify tetramer formation as a vulnerability for HbF silencing and provide opportunities for drug discovery.

A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.,Zheng G, Yin M, Mehta S, Chu IT, Wang S, AlShaye A, Drainville K, Buyanbat A, Bienfait F, Tenglin K, Zhu Q, Orkin SH Science. 2024 Nov 29;386(6725):1010-1018. doi: 10.1126/science.adp3025. Epub 2024 , Nov 28. PMID:39607926^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ. The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood. 2001 Dec 1;98(12):3413-20. PMID:11719382
↑ Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sanchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. Am J Hum Genet. 2016 Aug 4;99(2):253-74. doi: 10.1016/j.ajhg.2016.05.030. Epub, 2016 Jul 21. PMID:27453576 doi:https://dx.doi.org/10.1016/j.ajhg.2016.05.030
↑ Bauer DE, Orkin SH. Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Curr Opin Genet Dev. 2015 Aug;33:62-70. doi: 10.1016/j.gde.2015.08.001. Epub 2015, Sep 14. PMID:26375765 doi:https://dx.doi.org/10.1016/j.gde.2015.08.001
↑ Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sanchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. Am J Hum Genet. 2016 Aug 4;99(2):253-74. doi: 10.1016/j.ajhg.2016.05.030. Epub, 2016 Jul 21. PMID:27453576 doi:https://dx.doi.org/10.1016/j.ajhg.2016.05.030
↑ Zheng G, Yin M, Mehta S, Chu IT, Wang S, AlShaye A, Drainville K, Buyanbat A, Bienfait F, Tenglin K, Zhu Q, Orkin SH. A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing. Science. 2024 Nov 29;386(6725):1010-1018. PMID:39607926 doi:10.1126/science.adp3025

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Satterwhite E, Sonoki T, Willis TG, Harder L, Nowak R, Arriola EL, Liu H, Price HP, Gesk S, Steinemann D, Schlegelberger B, Oscier DG, Siebert R, Tucker PW, Dyer MJ. The BCL11 gene family: involvement of BCL11A in lymphoid malignancies. Blood. 2001 Dec 1;98(12):3413-20. PMID:11719382

[2] Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sanchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. Am J Hum Genet. 2016 Aug 4;99(2):253-74. doi: 10.1016/j.ajhg.2016.05.030. Epub, 2016 Jul 21. PMID:27453576 doi:https://dx.doi.org/10.1016/j.ajhg.2016.05.030

[3] Bauer DE, Orkin SH. Hemoglobin switching's surprise: the versatile transcription factor BCL11A is a master repressor of fetal hemoglobin. Curr Opin Genet Dev. 2015 Aug;33:62-70. doi: 10.1016/j.gde.2015.08.001. Epub 2015, Sep 14. PMID:26375765 doi:https://dx.doi.org/10.1016/j.gde.2015.08.001

[4] Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sanchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, Fisher SE, Logan DW. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. Am J Hum Genet. 2016 Aug 4;99(2):253-74. doi: 10.1016/j.ajhg.2016.05.030. Epub, 2016 Jul 21. PMID:27453576 doi:https://dx.doi.org/10.1016/j.ajhg.2016.05.030

[5] Zheng G, Yin M, Mehta S, Chu IT, Wang S, AlShaye A, Drainville K, Buyanbat A, Bienfait F, Tenglin K, Zhu Q, Orkin SH. A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing. Science. 2024 Nov 29;386(6725):1010-1018. PMID:39607926 doi:10.1126/science.adp3025

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9b4p

Tetramer Formation of the BCL11A ZF0 Domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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