High mobility group (HMG) box proteins are abundant and ubiquitous DNA binding proteins with a remarkable array of functions throughout the cell. The structure of the HMG-box DNA binding domain and general mechanisms of DNA binding and bending have been known for more than a decade. However, new mechanisms that regulate HMG-box protein intracellular translocation, and by which HMG-box proteins recognize DNA with and without sequence specificity, have only recently been uncovered. This review focuses primarily on the Sry-like HMG box family, HMGB1, and mitochondrial transcription factor A. For these proteins, structural and biochemical studies have shown that HMG-box protein modularity, interactions with other DNA binding proteins and cellular receptors, and post-translational modifications are key regulators of their diverse functions.

Mitochondrial transcription factor A (mtTFA/TFAM) is a nucleus-encoded, high-mobility-group-box (HMG-box) protein that regulates transcription of the mitochondrial genome by specifically recognizing light-strand and heavy-strand promoters (LSP, HSP1). TFAM also binds mitochondrial DNA in a non-sequence specific (NSS) fashion and facilitates its packaging into nucleoid structures. However, the requirement and contribution of DNA-bending for these two different binding modes has not been addressed in detail, which prompted this comparison of binding and bending properties of TFAM on promoter and non-promoter DNA. Promoter DNA increased the stability of TFAM to a greater degree than non-promoter DNA. However, the thermodynamic properties of DNA binding for TFAM with promoter and non-specific (NS) DNA were similar to each other and to other NSS HMG-box proteins. Fluorescence resonance energy transfer assays showed that TFAM bends promoter DNA to a greater degree than NS DNA. In contrast, TFAM lacking the C-terminal tail distorted both promoter and non-promoter DNA to a significantly reduced degree, corresponding with markedly decreased transcriptional activation capacity at LSP and HSP1 in vitro. Thus, the enhanced bending of promoter DNA imparted by the C-terminal tail is a critical component of the ability of TFAM to activate promoter-specific initiation by the core mitochondrial transcription machinery.

The multifunctional Creb-binding protein (CBP) protein plays a pivotal role in many critical cellular processes. Here we demonstrate that the bromodomain of CBP binds to histone H3 acetylated on lysine 56 (K56Ac) with higher affinity than to its other monoacetylated binding partners. We show that autoacetylation of CBP is critical for the bromodomain-H3 K56Ac interaction, and we propose that this interaction occurs via autoacetylation-induced conformation changes in CBP. Unexpectedly, the bromodomain promotes acetylation of H3 K56 on free histones. The CBP bromodomain also interacts with the histone chaperone anti-silencing function 1 (ASF1) via a nearby but distinct interface. This interaction is necessary for ASF1 to promote acetylation of H3 K56 by CBP, indicating that the ASF1-bromodomain interaction physically delivers the histones to the histone acetyl transferase domain of CBP. A CBP bromodomain mutation manifested in Rubinstein-Taybi syndrome has compromised binding to both H3 K56Ac and ASF1, suggesting that these interactions are important for the normal function of CBP. C hromatin is the physiological template for all genomic processes. The histone proteins that package the DNA into chromatin are subject to posttranslational modifications, including acetylation, methylation, phosphorylation, ubiquitination, and sumoylation, that serve to regulate DNA-templated phenomena such as transcription, replication, repair, and recombination (1). Many histone posttranslational modifications mediate their function by interacting specifically with and recruiting "reader" modules of multifunctional proteins, which often themselves have activities that subsequently further modify the chromatin structure to make the DNA either more or less accessible. For example, the bromodomain is the specific reader module for acetylated lysines on histones and nonhistone proteins (reviewed in ref.2), where acetylation is one of the most abundant posttranslational modifications in human cells.The bromodomain is found in many transcriptional coregulators and histone-modifying complexes, including histone acetyl transferases (HATs), enzymes that themselves mediate acetylation. Structural studies have revealed that bromodomains have a conserved structural fold that consists of a left-handed four-helix bundle and two interspersed ZA and BC loops which constitute the active acetyl lysine-binding pocket (3). Despite this conserved overall structure, different bromodomains recognize distinct acetylated lysines in different proteins because the specific amino acid residues within the loops of each bromodomain are critical for determining the acetyl lysine-binding specificity (4, 5).The general theme for bromodomain function is that they serve to anchor the bromodomain-containing protein to acetylated chromatin templates or to acetylated transcriptional activators. For example, the bromodomains of the yeast ATP-dependent nucleosome remodeler Swi2 and the HAT GCN5 are required for anchoring these chromatin-modifying complexes to acetylated c...

Information and organic molecules were the subject of two previous works from this lab (Graham and Schacht, J. Chem. Inf. Comput. Sci. 2000, 40, 187; Graham, J. Chem. Inf. Computer Sci. 2002, 42, 215). We delve further in this paper by examining organic structure graphs as objects of Brownian information processing. In so doing, tools are introduced which quantify and correlate molecular information to several orders. When the results are combined with energy data, an enhanced informatic view of covalent bond networks is obtained. The information properties of select molecules and libraries are illustrated. Notably, Brownian processing accommodates all possible compounds and libraries, not just ones registered in chemical databases. This approach establishes important features of the statistical structure underlying carbon chemistry.