Intrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains.

TitleIntrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains.
Publication TypeJournal Article
Year of Publication2019
AuthorsSzabo, B., T. Horvath, E. Schad, N. Murvai, Á. Tantos, L. Kalmar, L. Beatriz Chemes, K-H. Han, and P. Tompa
JournalInt J Mol Sci
Volume20
Issue9
Date Published2019 Apr 29
ISSN1422-0067
KeywordsAdenosine Triphosphate, Amino Acid Sequence, Binding Sites, Cellulase, Chemical Phenomena, Conserved Sequence, Enzymes, Intrinsically Disordered Proteins, Models, Molecular, Protein Binding, Protein Conformation, Protein Interaction Domains and Motifs, Structure-Activity Relationship
Abstract

(1) Background: Processivity is common among enzymes and mechanochemical motors that synthesize, degrade, modify or move along polymeric substrates, such as DNA, RNA, polysaccharides or proteins. Processive enzymes can make multiple rounds of modification without releasing the substrate/partner, making their operation extremely effective and economical. The molecular mechanism of processivity is rather well understood in cases when the enzyme structurally confines the substrate, such as the DNA replication factor PCNA, and also when ATP energy is used to confine the succession of molecular events, such as with mechanochemical motors. Processivity may also result from the kinetic bias of binding imposed by spatial confinement of two binding elements connected by an intrinsically disordered (ID) linker. (2) Method: By statistical physical modeling, we show that this arrangement results in processive systems, in which the linker ensures an optimized effective concentration around novel binding site(s), favoring rebinding over full release of the polymeric partner. (3) Results: By analyzing 12 such proteins, such as cellulase, and RNAse-H, we illustrate that in these proteins linker length and flexibility, and the kinetic parameters of binding elements, are fine-tuned for optimizing processivity. We also report a conservation of structural disorder, special amino acid composition of linkers, and the correlation of their length with step size. (4) Conclusion: These observations suggest a unique type of entropic chain function of ID proteins, that may impart functional advantages on diverse enzymes in a variety of biological contexts.

DOI10.3390/ijms20092119
Alternate JournalInt J Mol Sci
PubMed ID31032817
PubMed Central IDPMC6540235
Grant ListG.0029.12 / / Fonds Wetenschappelijk Onderzoek /
NTM2231611 / / National Research Council of Science and Technology /
K124670 / / Országos Tudományos Kutatási Alapprogramok /
K125340 / / Országos Tudományos Kutatási Alapprogramok /
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