2ypa
From Proteopedia
Structure of the SCL:E47:LMO2:LDB1 complex bound to DNA
Structural highlights
Disease[TAL1_HUMAN] Precursor T-cell acute lymphoblastic leukemia. A chromosomal aberration involving TAL1 may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). Translocation t(1;14)(p32;q11) with T-cell receptor alpha chain (TCRA) genes. [RBTN2_HUMAN] A chromosomal aberration involving LMO2 may be a cause of a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(11,14)(p13;q11) with TCRD. [TFE2_HUMAN] Precursor B-cell acute lymphoblastic leukemia. Chromosomal aberrations involving TCF3 are cause of forms of pre-B-cell acute lymphoblastic leukemia (B-ALL). Translocation t(1;19)(q23;p13.3) with PBX1. TCF3-PBX1 transforms cells by constitutively activating transcription of genes regulated by PBX1 or by other members of the PBX protein family. Translocation t(17;19)(q22;p13.3) with HLF. Inversion inv(19)(p13;q13) with TFPT. Function[LDB1_HUMAN] Binds to the LIM domain of a wide variety of LIM domain-containing transcription factors. May regulate the transcriptional activity of LIM-containing proteins by determining specific partner interactions. Play a role in the development of interneurons and motor neurons in cooperation with LHX3 and ISL1. Acts synergistically with LHX1/LIM1 in axis formation and activation of gene expression. Acts with LMO2 in the regulation of red blood cell development, maintaining erythroid precursors in an immature state (By similarity). [TAL1_HUMAN] Implicated in the genesis of hemopoietic malignancies. It may play an important role in hemopoietic differentiation. Serves as a positive regulator of erythroid differentiation (By similarity).[1] [RBTN2_HUMAN] Acts with TAL1/SCL to regulate red blood cell development. Also acts with LDB1 to maintain erythroid precursors in an immature state. [TFE2_HUMAN] Transcriptional regulator. Involved in the initiation of neuronal differentiation. Heterodimers between TCF3 and tissue-specific basic helix-loop-helix (bHLH) proteins play major roles in determining tissue-specific cell fate during embryogenesis, like muscle or early B-cell differentiation. Dimers bind DNA on E-box motifs: 5'-CANNTG-3'. Binds to the kappa-E2 site in the kappa immunoglobulin gene enhancer. Binds to IEB1 and IEB2, which are short DNA sequences in the insulin gene transcription control region. Publication Abstract from PubMedCell fate is governed by combinatorial actions of transcriptional regulators assembling into multiprotein complexes. However, the molecular details of how these complexes form are poorly understood. One such complex, which contains the basic-helix-loop-helix heterodimer SCL:E47 and bridging proteins LMO2:LDB1, critically regulates hematopoiesis and induces T cell leukemia. Here, we report the crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA, providing a molecular account of the network of interactions assembling this complex. This reveals an unexpected role for LMO2. Upon binding to SCL, LMO2 induces new hydrogen bonds in SCL:E47, thereby strengthening heterodimer formation. This imposes a rotation movement onto E47 that weakens the heterodimer:DNA interaction, shifting the main DNA-binding activity onto additional protein partners. Along with biochemical analyses, this illustrates, at an atomic level, how hematopoietic-specific SCL sequesters ubiquitous E47 and associated cofactors and supports SCL's reported DNA-binding-independent functions. Importantly, this work will drive the design of small molecules inhibiting leukemogenic processes. Structural Basis for LMO2-Driven Recruitment of the SCL:E47bHLH Heterodimer to Hematopoietic-Specific Transcriptional Targets.,El Omari K, Hoosdally SJ, Tuladhar K, Karia D, Hall-Ponsele E, Platonova O, Vyas P, Patient R, Porcher C, Mancini EJ Cell Rep. 2013 Jul 11;4(1):135-47. doi: 10.1016/j.celrep.2013.06.008. Epub 2013, Jul 3. PMID:23831025[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Human | Hoosdally, S J | Karia, D | Mancini, E J | Omari, K El | Patient, R | Platonova, O | Ponsele, E | Porcher, C | Tuladhar, K | Vyas, P | Hematopoiesis | Immune system | Leukemia
