Pro isomerization in MLL1 PHD3-Bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression Journal Article

   

Authors:	Wang, Z.; Song, J.; Milne, T. A.; Wang, G. G.; Li, H.; Allis, C. D.; Patel, D. J.
Article Title:	Pro isomerization in MLL1 PHD3-Bromo cassette connects H3K4me readout to CyP33 and HDAC-mediated repression
Abstract:	The MLL1 gene is a frequent target for recurrent chromosomal translocations, resulting in transformation of hematopoietic precursors into leukemia stem cells. Here, we report on structure-function studies that elucidate molecular events in MLL1 binding of histone H3K4me3/2 marks and recruitment of the cyclophilin CyP33. CyP33 contains a PPIase and a RRM domain and regulates MLL1 function through HDAC recruitment. We find that the PPIase domain of CyP33 regulates the conformation of MLL1 through proline isomerization within the PHD3-Bromo linker, thereby disrupting the PHD3-Bromo interface and facilitating binding of the MLL1-PHD3 domain to the CyP33-RRM domain. H3K4me3/2 and CyP33-RRM target different surfaces of MLL1-PHD3 and can bind simultaneously to form a ternary complex. Furthermore, the MLL1-CyP33 interaction is required for repression of HOXA9 and HOXC8 genes in vivo. Our results highlight the role of PHD3-Bromo cassette as a regulatory platform, orchestrating MLL1 binding of H3K4me3/2 marks and cyclophilin-mediated repression through HDAC recruitment. © 2010 Elsevier Inc.
Keywords:	controlled study; unclassified drug; human cell; methylation; protein conformation; protein domain; protein function; proteins; gene targeting; signaling; protein targeting; cell line; protein binding; transcription factor; in vivo study; protein interaction; stem cell; molecular mechanics; dna; amino acid sequence; molecular sequence data; histone h3; leukemia cell; gene repression; nuclear magnetic resonance spectroscopy; chromosome translocation; crystal structure; models, molecular; crystallography, x-ray; hematopoietic stem cell; protein structure; malignant transformation; histones; histone deacetylases; protein interaction domains and motifs; histone deacetylase; proline; x ray analysis; isomerization; nuclear magnetic resonance, biomolecular; cyclophilin; transcription factor hoxa9; mixed lineage leukemia protein; peptidylprolyl isomerase; procollagen proline 2 oxoglutarate 4 dioxygenase; transcription factor hoxc8; isothermal titration calorimetry; cyclophilins; myeloid-lymphoid leukemia protein
Journal Title:	Cell
Volume:	141
Issue:	7
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2010-06-25
Start Page:	1183
End Page:	1194
Language:	English
DOI:	10.1016/j.cell.2010.05.016
PUBMED:	20541251
PROVIDER:	scopus
PMCID:	PMC4690531
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-77953912031&partnerID=40&md5=e1c06afc055e0fde7912796c53873cb1
Notes:	--- - "Cited By (since 1996): 5" - "Export Date: 20 April 2011" - "CODEN: CELLB" - "Source: Scopus"

https://synapse.mskcc.org/synapse/works/has_related_data_chk/5331