Effects of molecular crowding on the structures, interactions, and functions of nucleic acids.

Epistasis plays an important role in the genetic architecture of common human diseases and can be viewed from two perspectives, biological and statistical, each derived from and leading to different assumptions and research strategies. Biological epistasis is the result of physical interactions among biomolecules within gene regulatory networks and biochemical pathways in an individual such that the effect of a gene on a phenotype is dependent on one or more other genes. In contrast, statistical epistasis is defined as deviation from additivity in a mathematical model summarizing the relationship between multilocus genotypes and phenotypic variation in a population. The goal of this essay is to review definitions and examples of biological and statistical epistasis and to explore the relationship between the two. Specifically, we present and discuss the following two questions in the context of human health and disease. First, when does statistical evidence of epistasis in human populations imply underlying biomolecular interactions in the etiology of disease? Second, when do biomolecular interactions produce patterns of statistical epistasis in human populations? Answers to these two reciprocal questions will provide an important framework for using genetic information to improve our ability to diagnose, prevent and treat common human diseases. We propose that systems biology will provide the necessary information for addressing these questions and that model systems such as bacteria, yeast and digital organisms will be a useful place to start.

Traversing the conceptual divide between biological and statistical epistasis: systems biology and a more modern synthesis.

Intrinsically disordered proteins (IDPs) and intrinsically disordered protein regions (IDPRs) are functional proteins and domains that devoid stable secondary and/or tertiary structure. IDPs/IDPRs are abundantly present in various proteomes, where they are involved in regulation, signaling, and control, thereby serving as crucial regulators of various cellular processes. Various mechanisms are utilized to tightly regulate and modulate biological functions, structural properties, cellular levels, and localization of these important controllers. Among these regulatory mechanisms are precisely controlled degradation and different posttranslational modifications (PTMs). Many normal cellular processes are associated with the presence of the right amounts of precisely activated IDPs at right places and in right time. However, wrecked regulation of IDPs/IDPRs might be associated with various human maladies, ranging from cancer and neurodegeneration to cardiovascular disease and diabetes. Pathogenic transformations of IDPs/IDPRs are often triggered by altered PTMs. This review considers some of the aspects of IDPs/IDPRs and their normal and aberrant regulation by PTMs.

/pdf/intrinsic-disorder-and-posttranslational-modifications-the-4dyuf6xpre.pdf

Intrinsic Disorder and Posttranslational Modifications: The Darker Side of the Biological Dark Matter.

Theory of biomolecular recognition.

Models for genetic regulation and cell fate specification characteristically assume that gene regulatory networks (GRNs) are essentially deterministic and exhibit multiple stable states specifying alternative, but pre-figured cell fates. Mounting evidence shows, however, that most eukaryotic precursor RNAs undergo alternative splicing (AS) and that the majority of transcription factors contain intrinsically disordered protein (IDP) domains whose functionalities are context dependent as well as subject to post-translational modification (PTM). Consequently, many transcription factors do not have fixed cis-acting regulatory targets, and developmental determination by GRNs alone is untenable. Modeling these phenomena requires a multi-scale approach to explain how GRNs operationally interact with the intra- and intercellular environments. Evidence shows that AS, IDP, and PTM complicate gene expression and act synergistically to facilitate and promote time- and cell-specific protein modifications involved in cell signaling and cell fate specification and thereby disrupt a strict deterministic GRN-phenotype mapping. The combined effects of AS, IDP, and PTM give proteomes physiological plasticity, adaptive responsiveness, and developmental versatility without inefficiently expanding genome size. They also help us understand how protein functionalities can undergo major evolutionary changes by buffering mutational consequences.

/pdf/rethinking-gene-regulatory-networks-in-light-of-alternative-wu32wobq9e.pdf

Rethinking gene regulatory networks in light of alternative splicing, intrinsically disordered protein domains, and post-translational modifications.

Hox Transcription Factor Ultrabithorax Ib Physically and Genetically Interacts with Disconnected Interacting Protein 1, a Double-stranded RNA-binding Protein

Characterization of their transcription activation domains is critical to understanding functional specificity within the Hox family of proteins. However, few Hox activation domains have been identified and none characterized in detail. In this study, promotor-reporter assays in yeast and Drosophila S2 cell culture were used to refine the boundaries of the activation domain of the Drosophila Hox protein Ultrabithorax (Ubx) and to identify critical elements within this domain. We found that residues 159-242 were sufficient for 50% function, and full transactivation capacity was achieved with inclusion of additional N-terminal sequences. Activation domain sequence and placement relative to the homeodomain differ between Ubx and other Hox proteins, consistent with the possibility that diverse activation mechanisms contribute to functional distinctions in vivo. The essential residues 159-242 in the UbxIb activation domain are predicted to contain a beta-sheet segment followed by an alpha-helix. This putative alpha-helical region was established to be necessary, but not sufficient, for transcriptional activation. Disruption of the helix by proline substitutions abolished activation function, while alteration of side chains presented on the surface of this putative helix with alanine or lysine mutations had no significant effect on activity. Collectively, these data indicate that this secondary structural element is a key component in forming an effective activation domain in the UbxIb protein. Interestingly, the alpha-helix critical for transcriptional activation is found only for Ubx orthologs from flies and not other species. The mutant Ubx proteins generated in this study have potential applications in deciphering Hox functions in vivo.

Transcription activation by ultrabithorax Ib protein requires a predicted α-helical region

Ultrabithorax (Ubx) and Deformed (Dfd) proteins of Drosophila melanogaster contain homeodomains (HD) that are structurally similar and recognize similar DNA sequences, despite functionally distinct genetic regulatory roles for Ubx and Dfd. We report in the present study that Ubx-HD binding to a single optimal target site displayed significantly increased affinity and higher salt concentration dependence at lower pH, while Dfd-HD binding to DNA was unaffected by pH. Results from studies of chimeric Ubx−Dfd homeodomains showed that the N- and C-terminal regions of the Ubx-HD are required for this pH dependence. The increase in binding affinity at lower pH was greater for the Ubx optimal binding site than for other DNA binding sites, indicating that subtle sequence alterations in DNA binding sites may influence pH-dependent behavior. These data demonstrate enhanced DNA binding affinity at lower pH for the Ubx-HD in vitro and suggest the potential for significant discrimination of DNA binding sites in vivo.

pH-Dependent Enhancement of DNA Binding by the Ultrabithorax Homeodomain†

The amino acid sequences of the homeodomains (HD) within the Ultrabithorax (Ubx) and Deformed (Dfd) proteins from Drosophila melanogaster are highly conserved despite distinct genetic regulatory functions for these proteins in embryonic development. We reported recently that Ubx-HD binding to a single target site displayed significantly increased affinity and greater salt concentration dependence at lower pH; in contrast, Dfd-HD did not show pH dependence in its DNA binding properties [Li, L., et al. (1996) Biochemistry 35, 9832-9839]. We demonstrate in this study that water activity differentially affects Ubx-HD and Dfd-HD DNA binding affinity. The sensitivity of the protein-DNA binding constant to osmotic pressures generated by neutral solutes was measured, and the formation of the Ubx-HD-DNA complex is associated with significantly greater water release than that of the Dfd-HD-DNA complex. No influence of pH on water release was detected for either HD. Experiments with chimeric Ubx-Dfd homeodomains demonstrated that the C-terminal region of the Ubx-HD is the primary determinant for the greater water release associated with DNA binding for this protein. DNA sequences do not exert a significant effect on the magnitude of water release associated with protein-DNA binding for Ubx-HD and the chimeric HD, UDU.

Differences in water release with DNA binding by ultrabithorax and deformed homeodomains.

Characterization of Mutants Affecting the KRK Sequence in the Carboxyl-terminal Domain of lac Repressor

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