7ZRY

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

Summary for 7ZRY

• Entry DOI: 10.2210/pdb7zry/pdb
• Descriptor: Isoform of Lysine-specific histone demethylase 1A, REST corepressor 1, FLAVIN-ADENINE DINUCLEOTIDE (3 entities in total)
• Functional Keywords: demethylase, histone, splicing, epigenetics, flavoprotein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 115850.57

Authors

Caroli, J.,Mattevi, A. (deposition date: 2022-05-06, release date: 2022-08-03, Last modification date: 2024-01-31)

Primary citation

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, 25:104665-104665, 2022

PubMed Abstract: 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.

PubMed: 35856020
DOI: 10.1016/j.isci.2022.104665

Experimental method

X-RAY DIFFRACTION (2.7 Å)