Browsing by Subject "Protein disorder"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Entropy, Fluctuations, and Disordered Proteins
    (MDPI, 2019-08) Faraggi, Eshel; Dunker, A. Keith; Jernigan, Robert L.; Kloczkowski, Andrzej; Physics, School of Science
    Entropy should directly reflect the extent of disorder in proteins. By clustering structurally related proteins and studying the multiple-sequence-alignment of the sequences of these clusters, we were able to link between sequence, structure, and disorder information. We introduced several parameters as measures of fluctuations at a given MSA site and used these as representative of the sequence and structure entropy at that site. In general, we found a tendency for negative correlations between disorder and structure, and significant positive correlations between disorder and the fluctuations in the system. We also found evidence for residue-type conservation for those residues proximate to potentially disordered sites. Mutation at the disorder site itself appear to be allowed. In addition, we found positive correlation for disorder and accessible surface area, validating that disordered residues occur in exposed regions of proteins. Finally, we also found that fluctuations in the dihedral angles at the original mutated residue and disorder are positively correlated while dihedral angle fluctuations in spatially proximal residues are negatively correlated with disorder. Our results seem to indicate permissible variability in the disordered site, but greater rigidity in the parts of the protein with which the disordered site interacts. This is another indication that disordered residues are involved in protein function.
  • Thumbnail Image
    Item
    Enzyme catalysis prior to aromatic residues: Reverse engineering of a dephospho-CoA kinase
    (Wiley, 2021) Makarov, Mikhail; Meng, Jingwei; Tretyachenko, Vyacheslav; Srb, Pavel; Březinová, Anna; Giacobelli, Valerio Guido; Bednárová, Lucie; Vondrášek, Jiří; Dunker, A. Keith; Hlouchová, Klára; Biochemistry and Molecular Biology, School of Medicine
    The wide variety of protein structures and functions results from the diverse properties of the 20 canonical amino acids. The generally accepted hypothesis is that early protein evolution was associated with enrichment of a primordial alphabet, thereby enabling increased protein catalytic efficiencies and functional diversification. Aromatic amino acids were likely among the last additions to genetic code. The main objective of this study was to test whether enzyme catalysis can occur without the aromatic residues (aromatics) by studying the structure and function of dephospho-CoA kinase (DPCK) following aromatic residue depletion. We designed two variants of a putative DPCK from Aquifex aeolicus by substituting (a) Tyr, Phe and Trp or (b) all aromatics (including His). Their structural characterization indicates that substituting the aromatics does not markedly alter their secondary structures but does significantly loosen their side chain packing and increase their sizes. Both variants still possess ATPase activity, although with 150-300 times lower efficiency in comparison with the wild-type phosphotransferase activity. The transfer of the phosphate group to the dephospho-CoA substrate becomes heavily uncoupled and only the His-containing variant is still able to perform the phosphotransferase reaction. These data support the hypothesis that proteins in the early stages of life could support catalytic activities, albeit with low efficiencies. An observed significant contraction upon ligand binding is likely important for appropriate organization of the active site. Formation of firm hydrophobic cores, which enable the assembly of stably structured active sites, is suggested to provide a selective advantage for adding the aromatic residues.
  • Thumbnail Image
    Item
    Evolution of Protein Ductility in Duplicated Genes of Plants
    (Frontiers, 2018-08-20) Yruela, Inmaculada; Contreras-Moreira, Bruno; Dunker, A. Keith; Niklas, Karl J.; Biochemistry and Molecular Biology, School of Medicine
    Previous work has shown that ductile/intrinsically disordered proteins (IDPs) and residues (IDRs) are found in all unicellular and multicellular organisms, wherein they are essential for basic cellular functions and complement the function of rigid proteins. In addition, computational studies of diverse phylogenetic lineages have revealed: (1) that protein ductility increases in concert with organismic complexity, and (2) that distributions of IDPs and IDRs along the chromosomes of plant species are non-random and correlate with variations in the rates of the genetic recombination and chromosomal rearrangement. Here, we show that approximately 50% of aligned residues in paralogs across a spectrum of algae, bryophytes, monocots, and eudicots are IDRs and that a high proportion (ca. 60%) are in disordered segments greater than 30 residues. When three types of IDRs are distinguished (i.e., identical, similar and variable IDRs) we find that species with large numbers of chromosome and endoduplicated genes exhibit paralogous sequences with a higher frequency of identical IDRs, whereas species with small chromosomes numbers exhibit paralogous sequences with a higher frequency of similar and variable IDRs. These results are interpreted to indicate that genome duplication events influence the distribution of IDRs along protein sequences and likely favor the presence of identical IDRs (compared to similar IDRs or variable IDRs). We discuss the evolutionary implications of gene duplication events in the context of ductile/disordered residues and segments, their conservation, and their effects on functionality.