Proof of principle in a de novo designed protein maquette: an allosterically regulated, charge-activated conformational switch in a tetra-alpha-helix bundle

Biochemistry
A M GrossetP Leslie Dutton

Abstract

New understanding of the engineering and allosteric regulation of natural protein conformational switches (such as those that couple chemical and ionic signals, mechanical force, and electro/chemical free energy for biochemical activation, catalysis, and motion) can be derived from simple de novo designed synthetic protein models (maquettes). We demonstrate proof of principle of both reversible switch action and allosteric regulation in a tetra-alpha-helical bundle protein composed of two identical di-helical subunits containing heme coordinated at a specific position close to the disulfide loop region. Individual bundles assume one of two switch states related by large-scale mechanical changes: a syn-topology (helices of the different subunits parallel) or anti-topology (helices antiparallel). Both the spectral properties of a coproporphyrin probe appended to the loop region and the distance-dependent redox interaction between the hemes identify the topologies. Beginning from a syn-topology, introduction of ferric heme in each subunit (either binding or redox change) shifts the topological balance by 25-50-fold (1.9-2.3 kcal/mol) to an anti-dominance. Charge repulsion between the two internal cationic ferric hemes drives the s...Continue Reading

References

Feb 1, 1997·Current Opinion in Structural Biology·M A KercherM Lewis
Jul 1, 1998·Annual Review of Biophysics and Biomolecular Structure·M F PerutzG G Dodson
May 13, 1999·Proceedings of the National Academy of Sciences of the United States of America·S T WalshW F DeGrado

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Citations

Dec 4, 2003·Current Opinion in Chemical Biology·Bohdana M DischerP Leslie Dutton
Sep 2, 2003·Current Opinion in Structural Biology·Paul D Barker
Mar 20, 2009·Nature·Ronald L KoderP Leslie Dutton
Apr 2, 2004·Proceedings of the National Academy of Sciences of the United States of America·Steve S HuangP Leslie Dutton
Oct 15, 2013·Nature Chemical Biology·Tammer A FaridP Leslie Dutton
Aug 7, 2012·The Journal of Physical Chemistry. B·Cynthia V Pagba, Bridgette A Barry
Jun 21, 2006·Dalton Transactions : an International Journal of Inorganic Chemistry·Ronald L Koder, P Leslie Dutton
Feb 6, 2014·Journal of the American Chemical Society·Lee A SolomonP Leslie Dutton
Nov 12, 2015·Biochimica Et Biophysica Acta·Daniel W WatkinsJ L Ross Anderson
May 24, 2012·Biochemical Society Transactions·Bruce R LichtensteinP Leslie Dutton
May 16, 2017·Journal of the American Chemical Society·Lee A SolomonH Christopher Fry
Nov 22, 2008·Biochemical Society Transactions·J L Ross AndersonP Leslie Dutton

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