Intrinsically disordered linkers impart processivity on enzymes by spatial confinement of binding domains

Beata Szabo, Tamas Horvath, Eva Schad, Nikoletta Murvai, Agnes Tantos, L. Kalmár, Lucía Beatriz Chemes, Kyou Hoon Han, Peter Tompa

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number2119
JournalInternational journal of molecular sciences
Volume20
Issue number9
DOIs
Publication statusPublished - May 1 2019

Fingerprint

enzymes
Enzymes
proteins
Proteins
DNA
Substrates
deoxyribonucleic acid
Intrinsically Disordered Proteins
Cellulase
adenosine triphosphate
polysaccharides
Adenosinetriphosphate
Proliferating Cell Nuclear Antigen
kinetics
releasing
Binding sites
Polysaccharides
RNA
DNA Replication
Kinetic parameters

Keywords

  • Binding domain
  • Binding motif
  • Disordered linker
  • Enzyme efficiency
  • Local effective concentration
  • Polymeric substrate
  • Processive enzyme
  • Spatial search

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Intrinsically disordered linkers impart processivity on enzymes by spatial confinement of binding domains. / Szabo, Beata; Horvath, Tamas; Schad, Eva; Murvai, Nikoletta; Tantos, Agnes; Kalmár, L.; Chemes, Lucía Beatriz; Han, Kyou Hoon; Tompa, Peter.

In: International journal of molecular sciences, Vol. 20, No. 9, 2119, 01.05.2019.

Research output: Contribution to journalArticle

Szabo, Beata ; Horvath, Tamas ; Schad, Eva ; Murvai, Nikoletta ; Tantos, Agnes ; Kalmár, L. ; Chemes, Lucía Beatriz ; Han, Kyou Hoon ; Tompa, Peter. / Intrinsically disordered linkers impart processivity on enzymes by spatial confinement of binding domains. In: International journal of molecular sciences. 2019 ; Vol. 20, No. 9.
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