Known allosteric proteins have central roles in genetic disease

Allostery is a form of protein regulation, where ligands that bind sites located apart from the active site can modify the activity of the protein. The molecular mechanisms of allostery have been extensively studied, because allosteric sites are less conserved than active sites, and drugs targeting them are more specific than drugs binding the active sites. Here we quantify the importance of allostery in genetic disease. We show that 1) known allosteric proteins are central in disease networks, and contribute to genetic disease and comorbidities much more than non-allosteric proteins, in many major disease types like hematopoietic diseases, cardiovascular diseases, cancers, diabetes, or diseases of the central nervous system. 2) variants from cancer genome-wide association studies are enriched near allosteric proteins, indicating their importance to polygenic traits; and 3) the importance of allosteric proteins in disease is due, at least partly, to their central positions in protein-protein interaction networks, and probably not due to their dynamical properties

Analysis of the largest tandemly repeated DNA families in the human genome

<p>Abstract</p> <p>Background</p> <p>Tandemly Repeated DNA represents a large portion of the human genome, and accounts for a significant amount of copy number variation. Here we present a genome wide analysis of the largest tandem repeats found in the human genome sequence.</p> <p>Results</p> <p>Using Tandem Repeats Finder (TRF), tandem repeat arrays greater than 10 kb in total size were identified, and classified into simple sequence e.g. GAATG, classical satellites e.g. alpha satellite DNA, and locus specific VNTR arrays. Analysis of these large sequenced regions revealed that several "simple sequence" arrays actually showed complex domain and/or higher order repeat organization. Using additional methods, we further identified a total of 96 additional arrays with tandem repeat units greater than 2 kb (the detection limit of TRF), 53 of which contained genes or repeated exons. The overall size of an array of tandem 12 kb repeats which spanned a gap on chromosome 8 was found to be 600 kb to 1.7 Mbp in size, representing one of the largest non-centromeric arrays characterized. Several novel megasatellite tandem DNA families were observed that are characterized by repeating patterns of interspersed transposable elements that have expanded presumably by unequal crossing over. One of these families is found on 11 different chromosomes in >25 arrays, and represents one of the largest most widespread megasatellite DNA families.</p> <p>Conclusion</p> <p>This study represents the most comprehensive genome wide analysis of large tandem repeats in the human genome, and will serve as an important resource towards understanding the organization and copy number variation of these complex DNA families.</p

Supplementary data to "Ligand binding site structure shapes folding, assembly and degradation of homomeric protein complexes" by G. Abrusan and J.A. Marsh

The structure of ligand binding sites has profound consequences for the evolution of function of protein complexes, particularly in homomers. Homomers with multichain binding sites (MBS) are characterized with more conserved binding sites and quaternary structure, and qualitatively different allosteric pathways than homomers with singlechain binding sites (SBS) or monomers. Here we show that 1) MBS homomers have significantly more long-range residue-residue interactions than SBS homomers or monomers, indicating that they have more complex folds and are more prone for misfolding; 2) In humans the interactome of MBS homomers is enriched in proteins that aid folding and assembly, including chaperones and chaperonins; 3) The sequences and structures of MBS and SBS homomers show qualitatively different distributions of frustrated residues, aggregation prone regions and interface residues, indicating that their interactions with the proteostasis network are different, and suggesting that SBS homomers are folded and assembled cotranslationally, while MBS homomers are not, and rely on more advanced folding-assistance and quality control mechanisms by chaperones and chaperonins.Abrusan, Gyorgy; Marsh, Joseph. (2019). Supplementary data to "Ligand binding site structure shapes folding, assembly and degradation of homomeric protein complexes" by G. Abrusan and J.A. Marsh, [dataset]. University of Edinburgh. https://doi.org/10.7488/ds/253

Supplementary data to "Ligand binding site structure shapes allosteric signal transduction and the evolution of allostery in protein complexes" by G. Abrusan and J.A. Marsh

The structure of ligand binding sites has been shown to profoundly influence the evolution of function in homomeric protein complexes. Complexes with multi-chain binding sites (MBSs) have more conserved quaternary structure, more similar binding sites and ligands between homologues, and evolve new functions slower than homomers with single-chain binding sites (SBSs). Here, using in silico analyses of protein dynamics, we investigate whether ligand binding-site structure shapes allosteric signal transduction pathways (STPs), and whether the structural similarity of binding sites influences the evolution of allostery. Our analyses show that: 1) allostery is more frequent among MBS complexes than in SBS complexes, particularly in homomers; 2) in MBS homomers, semi-rigid communities and critical residues frequently connect interfaces and thus they are characterized by STPs that cross protein-protein interfaces, while SBS homomers usually not; 3) ligand binding alters community structure differently in MBS and SBS homomers; 4) allosteric proteins are more likely to have homologs with similar binding site than non-allosteric proteins, suggesting that binding site similarity is an important factor driving the evolution of allostery.Abrusan, Gyorgy; Marsh, Joseph. (2019). Supplementary data to "Ligand binding site structure shapes allosteric signal transduction and the evolution of allostery in protein complexes" by G. Abrusan and J.A. Marsh, [dataset]. University of Edinburgh. MRC Human Genetics Unit. https://doi.org/10.7488/ds/2493