Design of single-layer β-sheets without a hydrophobic core

Shohei Koide (), Xiaolin Huang, Karl Link, Akiko Koide, Zimei Bu and Donald M. Engelman
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Shohei Koide: Department of Biochemistry and Biophysics University of Rochester Medical Center
Xiaolin Huang: Department of Biochemistry and Biophysics University of Rochester Medical Center
Karl Link: Department of Biochemistry and Biophysics University of Rochester Medical Center
Akiko Koide: Department of Biochemistry and Biophysics University of Rochester Medical Center
Zimei Bu: Yale University
Donald M. Engelman: Yale University

Nature, 2000, vol. 403, issue 6768, 456-460

Abstract: Abstract The hydrophobic effect is the main thermodynamic driving force in the folding of water-soluble proteins1,2. Exclusion of nonpolar moieties from aqueous solvent results in the formation of a hydrophobic core in a protein, which has been generally considered essential for specifying and stabilizing the folded structures of proteins1,2,3,4,5,6. Outer surface protein A (OspA) from Borrelia burgdorferi contains a three-stranded β-sheet segment which connects two globular domains7. Although this single-layer β-sheet segment is exposed to solvent on both faces and thus does not contain a hydrophobic core, the segment has a high conformational stability8. Here we report the engineering of OspA variants that contain larger single-layer β-sheets (comprising five and seven β-strands) by duplicating a β-hairpin unit within the β-sheet. Nuclear magnetic resonance and small-angle X-ray scattering analyses reveal that these extended single-layer β-sheets are formed as designed, and amide hydrogen–deuterium exchange and chemical denaturation show that they are stable. Thus, interactions within the β-hairpin unit and those between adjacent units, which do not involve the formation of a hydrophobic core, are sufficient to specify and stabilize the single-layer β-sheet structure. Our results provide an expanded view of protein folding, misfolding and design.

Date: 2000
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DOI: 10.1038/35000255

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