title: Intermolecular β-strand networks avoid hub residues and favor low interconnectedness: a potential protection mechanism against chain dissociation upon mutation.
abstract: Altogether few protein oligomers undergo a conformational transition to a state that impairs their function and leads to diseases. But when it happens, the consequences are not harmless and the so-called conformational diseases pose serious public health problems. Notorious examples are the Alzheimer's disease and some cancers associated with a conformational change of the amyloid precursor protein (APP) and of the p53 tumor suppressor, respectively. The transition is linked with the propensity of β-strands to aggregate into amyloid fibers. Nevertheless, a huge number of protein oligomers associate chains via β-strand interactions (intermolecular β-strand interface) without ever evolving into fibers. We analyzed the layout of 1048 intermolecular β-strand interfaces looking for features that could provide the β-strands resistance to conformational transitions. The interfaces were reconstructed as networks with the residues as the nodes and the interactions between residues as the links. The networks followed an exponential decay degree distribution, implying an absence of hubs and nodes with few links. Such layout provides robustness to changes. Few links per nodes do not restrict the choices of amino acids capable of making an interface and maintain high sequence plasticity. Few links reduce the "bonding" cost of making an interface. Finally, few links moderate the vulnerability to amino acid mutation because it entails limited communication between the nodes. This confines the effects of a mutation to few residues instead of propagating them to many residues via hubs. We propose that intermolecular β-strand interfaces are organized in networks that tolerate amino acid mutation to avoid chain dissociation, the first step towards fiber formation. This is tested by looking at the intermolecular β-strand network of the p53 tetramer.
authors.affiliation: Laboratoire d'Annecy-le Vieux de physique théorique (LAPTH UMR 5108), Université de Savoie, CNRS, Annecy le Vieux, France.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Feverati
authors.affiliation: Laboratoire d'informatique systèmes, traitement de l'information et de la connaissance (LISTIC), Université de Savoie, Annecy le Vieux, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Achoch
authors.affiliation: Laboratoire de mathématiques (LAMA UMR 5127), Université de Savoie, CNRS, Le Bourget du Lac, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vuillon
authors.affiliation: Aging and imaging (AGIM FRE 3405), Université Joseph Fourier, CNRS, Grenoble, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Lesieur
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D000682:Amyloid / Q000737:chemistry*; D019295:Computational Biology; D030562:Databases, Protein; D006801:Humans; D008958:Models, Molecular; D015233:Models, Statistical; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D000682:Amyloid; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
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