Macro domains as metabolite sensors on chromatin

Abstract

How metabolism and epigenetics are molecularly linked and regulate each other is poorly understood. In this review, we will discuss the role of direct metabolite-binding to chromatin components and modifiers as a possible regulatory mechanism. We will focus on globular macro domains, which are evolutionarily highly conserved protein folds that can recognize NAD(+)-derived metabolites. Macro domains are found in histone variants, histone modifiers, and a chromatin remodeler among other proteins. Here we summarize the macro domain-containing chromatin proteins and the enzymes that generate relevant metabolites. Focusing on the histone variant macroH2A, we further discuss possible implications of metabolite binding for chromatin function.

Fig. 1

Human macro domain-containing proteins. a Schematic representation of the 12 human macro domain-containing proteins. b The topology view clearly shows the high conservation of the macro fold when comparing the human macro domains of macroH2A1.1 (3IID), MacroD1 (2X47), and PARP14 (N-terminal macro domain, 3Q6Z) with Af1521 (2BFQ) from the archaeon A. fulgidus. The core β-sheets are colored magenta, the core α-helices rose, and the variable structural elements grey. c, d Cartoon view and surface representation of macroH2A1.1 bound to ADPR (3IID). In d blue indicates nitrogens and red oxygens

Fig. 2

NAD⁺ metabolism. a Schematic representation of the NAD(H) redox pool and replenishing and consuming reactions. Arrows indicate enzymatic reactions. Enzymes are in italic type and metabolites are in regular type. Metabolites able to bind macro domains are highlighted in yellow. b Chemical structure of NAD⁺ indicating different moieties and reactive sites. The representation has been adapted from [146]. ADPR ADP ribose, ADPR1P ADPR-1-phosphate, LDH lactate dehydrogenase, NA nicotinic acid, NAD NAM adenine dinucleotide, NAMN NA mononucleotide, NAM nicotinamide, NAMPT NAM phosphoribosyltransferase, NR NAM riboside, NMN NAM mononucleotide, NMNAT NMN adenyltransferase, mADPRyl mono-ADP-ribosylated protein, OAADPR O-acetyl-ADPR, PAR poly-ADPR, PARG PAR glycohydrolase, PARP PAR polymerase, PARyl PARylated protein, PDE phosphodiesterase, RC respiratory chain, Trp tryptophan

Fig. 3

MacroH2A confers metabolite-binding capacity to the nucleosome. The linker domain protrudes out of the complex structure of the nucleosome and places the macro domain in an accessible position in close proximity to the dyad axis on the DNA entry side. The pockets of all three human macroH2A macro domains are shown. To visualize the binding pocket properties, the surface representations were sliced open. The protein interior is shown in black, and the interior of the pockets is colored according to the surface charges: red means acidic, blue basic, and white non-charged. The rest of the protein surface is shaded grey

Fig. 4

Metabolite binding to macroH2A1.1-containing chromatin. The macro domain of chromatin incorporated macroH2A1.1 is believed to be able to bind ADP ribosylated proteins, which include chromatin regulators and components. Free metabolites such as ADPR are likely to compete with these interactions. In addition, metabolite-binding also has the potential to affect direct interactions by inducing a conformational change of the macro domain