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Open AccessArticle

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

1
Institute of Enzymology, Center of Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
2
Instituto de Investigaciones Biotecnológicas IIB-INTECH, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Universidad Nacional de San Martín, Buenos Aires 1650, Argentina
3
Genome Editing Research Center, Division of Biomedical Science, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34113, Korea
4
Department of Nano and Bioinformatics, University of Science and Technology (UST), Daejeon 34113, Korea
5
VIB Center for Structural Biology, Vrije Univresiteit Brussel, 1050 Belgium, Brussel
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(9), 2119; https://doi.org/10.3390/ijms20092119
Received: 3 April 2019 / Revised: 24 April 2019 / Accepted: 26 April 2019 / Published: 29 April 2019
(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. View Full-Text
Keywords: enzyme efficiency; polymeric substrate; processive enzyme; disordered linker; binding motif; binding domain; spatial search; local effective concentration enzyme efficiency; polymeric substrate; processive enzyme; disordered linker; binding motif; binding domain; spatial search; local effective concentration
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Szabo, B.; Horvath, T.; Schad, E.; Murvai, N.; Tantos, A.; Kalmar, L.; Chemes, L.B.; Han, K.-H.; Tompa, P. Intrinsically Disordered Linkers Impart Processivity on Enzymes by Spatial Confinement of Binding Domains. Int. J. Mol. Sci. 2019, 20, 2119.

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