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Andreas G Ladurner

Publications and source records attributed to Andreas G Ladurner.

11 recordsLinked to original sources
PubMed2006

Rheostat control of gene expression by metabolites.

Organisms adapt to changes in environmental conditions by altering gene expression. Such homeostatic control is apparent in metabolism, where biosynthetic metabolites play a role in regulatory feedback loops. Increasing evidence shows that small-molecule metabolites also shape the structure of chromatin and directly regulate the transcription and translation processes. These endogenous metabolites bind specialized histones, are used as substrates by chromatin-modifying enzymes, regulate the activity of transcriptional corepressors, and even modulate the structure of RNA itself. In doing so, they act as dynamic rheostats that fine-tune the activity of hard-wired gene circuits. Metabolites emerge as key effectors in tweaking gene expression.

Adenine Nucleotides↗
PubMed2005

Splicing regulates NAD metabolite binding to histone macroH2A.

Histone macroH2A is a hallmark of mammalian heterochromatin. Here we show that human macroH2A1.1 binds the SirT1-metabolite O-acetyl-ADP-ribose (OAADPR) through its macro domain. The 1.6-A crystal structure and mutants reveal how the metabolite is recognized. Mutually exclusive exon use in the gene H2AFY produces macroH2A1.2, whose tissue distribution differs. MacroH2A1.2 shows only subtle structural changes but cannot bind nucleotides. Alternative splicing may thus regulate the binding of nicotinamide adenine dinucleotide (NAD) metabolites to chromatin.

Alternative Splicing↗
PubMed2005

The macro domain is an ADP-ribose binding module.

The ADP-ribosylation of proteins is an important post-translational modification that occurs in a variety of biological processes, including DNA repair, transcription, chromatin biology and long-term memory formation. Yet no protein modules are known that specifically recognize the ADP-ribose nucleotide. We provide biochemical and structural evidence that macro domains are high-affinity ADP-ribose binding modules. Our structural analysis reveals a conserved ligand binding pocket among the macro domain fold. Consistently, distinct human macro domains retain their ability to bind ADP-ribose. In addition, some macro domain proteins also recognize poly-ADP-ribose as a ligand. Our data suggest an important role for proteins containing macro domains in the biology of ADP-ribose.

Adenosine Diphosphate↗
PubMed2003

Mutations of penicillin acylase residue B71 extend substrate specificity by decreasing steric constraints for substrate binding.

Two mutant forms of penicillin acylase from Escherichia coli strains, selected using directed evolution for the ability to use glutaryl-L-leucine for growth [Forney, Wong and Ferber (1989) Appl. Environ. Microbiol. 55, 2550-2555], are changed within one codon, replacing the B-chain residue Phe(B71) with either Cys or Leu. Increases of up to a factor of ten in k (cat)/ K (m) values for substrates possessing a phenylacetyl leaving group are consistent with a decrease in K (s). Values of k (cat)/ K (m) for glutaryl-L-leucine are increased at least 100-fold. A decrease in k (cat)/ K (m) for the Cys(B71) mutant with increased pH is consistent with binding of the uncharged glutaryl group. The mutant proteins are more resistant to urea denaturation monitored by protein fluorescence, to inactivation in the presence of substrate either in the presence of urea or at high pH, and to heat inactivation. The crystal structure of the Leu(B71) mutant protein, solved to 2 A resolution, shows a flip of the side chain of Phe(B256) into the periphery of the catalytic centre, associated with loss of the pi-stacking interactions between Phe(B256) and Phe(B71). Molecular modelling demonstrates that glutaryl-L-leucine may bind with the uncharged glutaryl group in the S(1) subsite of either the wild-type or the Leu(B71) mutant but with greater potential freedom of rotation of the substrate leucine moiety in the complex with the mutant protein. This implies a smaller decrease in the conformational entropy of the substrate on binding to the mutant proteins and consequently greater catalytic activity.

Binding Sites↗
PubMed2003

Bromodomains mediate an acetyl-histone encoded antisilencing function at heterochromatin boundaries.

Bromodomains bind acetylated histone H4 peptides in vitro. Since many chromatin remodeling complexes and the general transcription factor TFIID contain bromodomains, they may link histone acetylation to increased transcription. Here we show that yeast Bdf1 bromodomains recognize endogenous acetyl-histone H3/H4 as a mechanism for chromatin association in vivo. Surprisingly, deletion of BDF1 or a Bdf1 mutation that abolishes histone binding leads to transcriptional downregulation of genes located at heterochromatin-euchromatin boundaries. Wild-type Bdf1 protein imposes a physical barrier to the spreading of telomere- and mating-locus-proximal SIR proteins. Biochemical experiments indicate that Bdf1 competes with the Sir2 deacetylase for binding to acetylated histone H4. These data suggest an active role for Bdf1 in euchromatin maintenance and antisilencing through a histone tail-encoded boundary function.

Acetylation↗
PubMed2003

Inactivating chromosomes: a macro domain that minimizes transcription.

The histone variant macroH2A plays a role in mammalian chromosome X inactivation. Recent data suggest its unusual C-terminal macro domain may be an enzyme that regulates the ADP-ribosylation of chromatin. MacroH2A could thus help correct gene dosage between males and females using a novel epigenetic mark.

Adenosine Diphosphate Ribose↗