7zry

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Structure of the 2a splicing variant of the full-length human LSD1 bound to CoREST (delta305)

Structural highlights

7zry is a 2 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 2.7Å
Ligands:FAD
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

RCOR1_HUMAN Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation.[1] [2] [3] [4] [5] [6] [7]

Publication Abstract from PubMed

The histone demethylase KDM1A is a multi-faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A(-/-) hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a(-/-) hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells.

Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism.,Astro V, Ramirez-Calderon G, Pennucci R, Caroli J, Saera-Vila A, Cardona-Londono K, Forastieri C, Fiacco E, Maksoud F, Alowaysi M, Sogne E, Falqui A, Gonzalez F, Montserrat N, Battaglioli E, Mattevi A, Adamo A iScience. 2022 Jun 23;25(7):104665. doi: 10.1016/j.isci.2022.104665. eCollection , 2022 Jul 15. PMID:35856020[8]

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

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Citations
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Demethylase-independent roles of LSD1 in regulating enhancers and cell fate transition.
Zeng et al. (2023)
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1 other articles
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See Also

References

  1. ↑ Ballas N, Battaglioli E, Atouf F, Andres ME, Chenoweth J, Anderson ME, Burger C, Moniwa M, Davie JR, Bowers WJ, Federoff HJ, Rose DW, Rosenfeld MG, Brehm P, Mandel G. Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001 Aug 16;31(3):353-65. PMID:11516394
  2. ↑ You A, Tong JK, Grozinger CM, Schreiber SL. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1454-8. PMID:11171972 doi:10.1073/pnas.98.4.1454
  3. ↑ Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5. PMID:12032298 doi:10.1073/pnas.112008599
  4. ↑ Lunyak VV, Burgess R, Prefontaine GG, Nelson C, Sze SH, Chenoweth J, Schwartz P, Pevzner PA, Glass C, Mandel G, Rosenfeld MG. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science. 2002 Nov 29;298(5599):1747-52. Epub 2002 Oct 24. PMID:12399542 doi:10.1126/science.1076469
  5. ↑ Hakimi MA, Dong Y, Lane WS, Speicher DW, Shiekhattar R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2003 Feb 28;278(9):7234-9. Epub 2002 Dec 18. PMID:12493763 doi:10.1074/jbc.M208992200
  6. ↑ Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005 Sep 16;19(6):857-64. PMID:16140033 doi:10.1016/j.molcel.2005.08.027
  7. ↑ Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005 Sep 15;437(7057):432-5. Epub 2005 Aug 3. PMID:16079794 doi:10.1038/nature04021
  8. ↑ Astro V, Ramirez-Calderon G, Pennucci R, Caroli J, Saera-Vila A, Cardona-Londono K, Forastieri C, Fiacco E, Maksoud F, Alowaysi M, Sogne E, Falqui A, Gonzalez F, Montserrat N, Battaglioli E, Mattevi A, Adamo A. Fine-tuned KDM1A alternative splicing regulates human cardiomyogenesis through an enzymatic-independent mechanism. iScience. 2022 Jun 23;25(7):104665. doi: 10.1016/j.isci.2022.104665. eCollection , 2022 Jul 15. PMID:35856020 doi:http://dx.doi.org/10.1016/j.isci.2022.104665

Contents


PDB ID 7zry

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