PT  - JOURNAL ARTICLE
AU  - Benjamin M. Lorton
AU  - Rajesh K. Harijan
AU  - Emmanuel S. Burgos
AU  - Jeffery B. Bonanno
AU  - Steven C. Almo
AU  - David Shechter
TI  - A binary arginine methylation switch on histone H3 Arginine 2 regulates its interaction with WDR5
AID  - 10.1101/2020.01.13.904581
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.01.13.904581
4099  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.904581.short
4100  - http://biorxiv.org/content/early/2020/01/14/2020.01.13.904581.full
AB  - Histone H3 arginine 2 (H3R2) is post-translationally modified in three different states by “writers” of the protein arginine methyltransferase (PRMT) family. H3R2 methylarginine isoforms include PRMT5-catalyzed mono- and symmetric di-methylation (me1, me2s), and PRMT6-catalyzed me1 and asymmetric dimethylation (me2a). WD-40 repeat-containing protein 5 (WDR5) is an epigenetic “reader” protein that interacts with H3R2 and is a subunit of numerous chromatin-modifying complexes, such as the Mixed Lineage Leukemia (MLL) H3 lysine 4 methyltransferase complex. Previous studies suggested that MLL recruitment to chromatin was specified by the high-affinity interaction between WDR5 and H3R2me2s. However, our prior biological data prompted the hypothesis that WDR5 may also interact with H3R2me1 to recruit MLL activity. Here, using highly accurate quantitative binding analysis combined with high-resolution crystal structures of WDR5 in complex with unmodified (me0) and me1/me2s L-Arginine amino acids and in complex with H3R2me1 peptide, we provide a rigorous biochemical study of this important biological interaction. Despite modest structural differences at the binding interface, our study supports an interaction model regulated by a binary arginine methylation switch: H3R2me2a prevents interaction with WDR5, whereas H3R2me0/me1/me2s are equally permissive.ABBREVIATIONSH3histone H3HPLChigh performance liquid chromatographyITCisothermal titration calorimetryK4lysine 4Kd,equilibrium dissociation constantKANSLlysine acetyltransferase non-specific lethalMLLmixed lineage leukemiaNuRDnucleosome remodeling and deacetylasePRMTprotein arginine methyltransferaseR2arginine 2Rme1/MMAmonomethylarginineRme2s/sDMAsymmetric dimethylarginineRme2a/aDMAasymmetric dimethylarginineRMSDroot mean squared deviationWBMWDR5 binding motifWDR5WD-40 repeat-containing protein 5WINWDR5 interacting.