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Nature
Article . 2019 . Peer-reviewed
License: Springer TDM
Data sources: Crossref
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Nature
Article . 2020
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Low-barrier hydrogen bonds in enzyme cooperativity

Authors: Fabian Rabe von Pappenheim; Fabian Rabe von Pappenheim; Kai Tittmann; Kai Tittmann; Viktor Sautner; Viktor Sautner; Lisa-Marie Funk; +7 Authors

Low-barrier hydrogen bonds in enzyme cooperativity

Abstract

The underlying molecular mechanisms of cooperativity and allosteric regulation are well understood for many proteins, with haemoglobin and aspartate transcarbamoylase serving as prototypical examples1,2. The binding of effectors typically causes a structural transition of the protein that is propagated through signalling pathways to remote sites and involves marked changes on the tertiary and sometimes even the quaternary level1-5. However, the origin of these signals and the molecular mechanism of long-range signalling at an atomic level remain unclear5-8. The different spatial scales and timescales in signalling pathways render experimental observation challenging; in particular, the positions and movement of mobile protons cannot be visualized by current methods of structural analysis. Here we report the experimental observation of fluctuating low-barrier hydrogen bonds as switching elements in cooperativity pathways of multimeric enzymes. We have observed these low-barrier hydrogen bonds in ultra-high-resolution X-ray crystallographic structures of two multimeric enzymes, and have validated their assignment using computational calculations. Catalytic events at the active sites switch between low-barrier hydrogen bonds and ordinary hydrogen bonds in a circuit that consists of acidic side chains and water molecules, transmitting a signal through the collective repositioning of protons by behaving as an atomistic Newton's cradle. The resulting communication synchronizes catalysis in the oligomer. Our studies provide several lines of evidence and a working model for not only the existence of low-barrier hydrogen bonds in proteins, but also a connection to enzyme cooperativity. This finding suggests new principles of drug and enzyme design, in which sequences of residues can be purposefully included to enable long-range communication and thus the regulation of engineered biomolecules.

Country
Germany
Keywords

Models, Molecular, Pyruvate Oxidase, Hydrogen Bonding, Molecular Dynamics Simulation, Crystallography, X-Ray, Protein Structure, Tertiary, Catalytic Domain, Mutation, Escherichia coli, Humans, Transketolase, info:eu-repo/classification/ddc/530, Lactobacillus plantarum

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citations
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
92
Top 1%
Top 10%
Top 1%
Green