Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases

Abstract

The human KDM7 subfamily histoneH 3N emethyll ysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer.W ed escribe experimentally basedc omputational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity.F 279S an Xlinked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligandsa nd second sphere residues. The calculations revealkey roles of aflexible protein environment in productive formation of enzyme-substrate complexes and suggest targeting the flexible KDM7 linker region is of interest from am edicinal chemistry perspective.The methylation states of Lys-and Arg-residues on histones can have profound effects on the structures and functions of chromatin, with consequences for expression in healthy and diseased tissues. [1a, 2] Methyl transferases and demethylases regulate histone methylation status. The largestf amily of Nemethyl Lys-demethylases (KDMs)b elongs to as uperfamily of non-hemeF e II dependento xygenases, which catalyzeawide range of reactions including hydroxylations, deoxygenations, ring formations, halogenations, and demethylations, normally coupled to 2-oxoglutarate (2OG) cosubstrate oxidation. [1a, 2, 3]

What Is the Catalytic Mechanism of Enzymatic Histone N‐Methyl Arginine Demethylation and Can It Be Influenced by an External Electric Field?

“…The mechanisms of dioxygen activation by non‐heme Fe (II) enzymes have been explored using experimental and computational methods; [2,12–14] however, there are no such studies reported on the recently reported JmjC KDM catalyzed histone arginine demethylation (RDM) reaction [15–17] . The 2OG oxygenases have evolved to activate O 2 to enable production of a ferryl intermediate that effects C−H bond cleavage, typically generating an alcohol product [7,12–14] .…”

“…The 2OG oxygenases have evolved to activate O 2 to enable production of a ferryl intermediate that effects C−H bond cleavage, typically generating an alcohol product [7,12–14] . Details of the mechanism leading to the ferryl intermediate and studies on model systems have been reported [15– 26a] . Following substrate binding, the consensus 2OG oxygenase mechanism [7,12– 26a–c] involves initial generation of a Fe(III)‐superoxo complex; oxidative decarboxylation of 2OG generates a Fe(II)‐peroxysuccinate intermediate which reacts to give a high‐spin (S=2) state ferryl intermediate, which abstracts a hydrogen atom from the substrate.…”

“…KDM4E [Figure 1] is a JmjC 2OG oxygenase that in addition to KDM activity, at least in isolated form, also has RDM activity, including as shown by its demethylation of a histone H4 fragment with a symmetrically dimethylated arginine at residue R3 (H4R3me2 s) [8] . The mechanisms of histone lysine demethylation (KDM) by 2OG‐demethylases have been recently explored, [15,16,18] providing insights into their reaction mechanisms, alternative mechanistic strategies, residues that stabilize the transition states, and long‐range correlated motions involved in their catalysis. KDM4E is a relatively efficient arginine demethylase (RDM), while KDM4A is a relatively more efficient lysine demethylase (KDM) [8] .…”

Production of ROS by Gallic Acid Activates KDM2A to Reduce rRNA Transcription

“…The JmjC-type KDMs are one group of α-ketoglutarate-dependent oxygenases that catalyze a remarkably diverse range of oxidative reactions [ 9 ]. The JmjC-type KDMs remove methyl groups on lysine in the specific amino acid stretches of histones, and the selectivity of substrates is determined by the structure of the JmjC domain and also the dynamics of the amino acid sequence near the JmjC domain [ 10 , 11 ]. KDMs also distinguish the number of methyl groups attached to lysine [ 7 ].…”

Regulation of histone H3 lysine 9 methylation in inflammation

“…The KDM7 enzymes have a PHD domain at the N-terminal, and JmjC at the C-terminal, both domains are dispensable for removing methyl group from H3K91/2. The KDM7A and KDM7B differ in flexibility and the length of their linker region (Chaturvedi et al 2019a(Chaturvedi et al , 2019b (Table 2). To be brief, H3K9 methyltransferases and demethylases act as 'writers' and 'erasers' to precisely balance H3K9 methylation status.…”