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Engineering protein stability with atomic precision in a monomeric miniprotein

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)764-770
Number of pages7
JournalNature Chemical Biology
Volume13
Journal issue7
Early online date22 May 2017
DOIs
StatePublished - 1 Jul 2017

Abstract

Miniproteins simplify the protein-folding problem, allowing the dissection of forces that stabilize protein structures. Here we describe PPα-Tyr, a designed peptide comprising an α helix buttressed by a polyproline-II helix. PPα-Tyr is water soluble, monomeric, and unfolds cooperatively with a midpoint unfolding temperature (TM) of 39 ˚C. NMR structures of PPα-Tyr reveal proline residues docked between tyrosine side chains as designed. The stability of PPα is sensitive to the aromatic residue: replacing tyrosine by phenylalanine, i.e. changing three solvent-exposed hydroxyl groups to protons, reduces the TM to 20 ˚C. We attribute this to the loss of CH–π interactions between the aromatic and proline rings, which we probe by substituting the aromatic residues with non-proteinogenic side chains. In analyses of natural protein structures we find a preference for proline-tyrosine interactions over other proline-containing pairs, and abundant CH–π interactions in biologically important complexes between proline-rich ligands and SH3 and similar domains.

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