9b4p
From Proteopedia
Tetramer Formation of the BCL11A ZF0 Domain
Structural highlights
DiseaseBC11A_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] FunctionBC11A_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 PubMedDown-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
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