A short linear peptide derived from the N-terminal sequence of ubiquitin folds into a water-stable non-native β-hairpin

Abstract

A 16-residue peptide derived from the N-terminal sequence of ubiquitin forms a stable monomeric beta-hairpin that is estimated to be approximately 80% populated in aqueous solution. The peptide sequence has been modified from native ubiquitin by replacing the five residues found in a type I G1 bulged turn (Thr-Leu-Thr-Gly-Lys) with four residues (Asn-Pro-Asp-Gly) to maximize the probability of forming a beta-turn. Unexpectedly, the bulged turn conformation is re-established in the beta-hairpin in solution with two consequences: a one-amino acid frameshift in the alignment of the peptide main chain occurs relative to the native hairpin, and side chains formerly on opposite faces of the hairpin are brought together on the same face. The presence of the bulged turn in native ubiquitin may help in the avoidance of the stable non-native register of amino acids found here which would be unproductive for folding.

Equilibrium folding intermediates of a greek key β-barrel protein

“…In the EF b-hairpin, backbone NH groups of residues Lys49, Ile51, Gln54, Gly57, Ala59 and Val65 do not show exchange, evidencing a single, stable conformation. Previous demonstrations that small peptides can form stable b-hairpins in aqueous solution (Blanco et al, 1994;Searle et al, 1995;Sieber & Moe, 1996) provide indirect evidence that the EF b-hairpin serves as a folding nucleus. The EF b-hairpin is one of four so-called folded hairpins which are a prominent feature of the protein S and bg-crystallin structures (Bagby et al, 1994a;Lapatto et al, 1991).…”

Prediction of local structure in proteins using a library of sequence-structure motifs

“…Experimental evidence for this comes from NMR studies of isolated peptides. For the most part, peptides of 30 residues or less are found not to have a well-de®ned structure in water (Itzhaki et al, 1995;Yang et al, 1995), but many of the notable exceptions correspond to I-sites motifs, including the Schellman cap (Viguera & Serrano, 1995), the N-capping box , the serine b-hairpin (Blanco et al, 1994), the type-I b-hairpin (de Alba et al, 1996;Ilyina et al, 1994;Searle et al, 1995), and the diverging type-II turn (Sieber & Moe, 1996). In each case, a predominant solution structure was found that closely resembled the paradigm structure of the I-sites cluster that best matched its sequence.…”

Cross-Strand Coupling and Site-Specific Unfolding Thermodynamics of a Trpzip β-Hairpin Peptide Using 13C Isotopic Labeling and IR Spectroscopy

“…Studies of isolated, water-soluble -hairpins can provide valuable insight into properties of -sheet structure and folding since -hairpins are considered to act as possible nucleation sites for protein folding. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] Additionally, their detailed structural interactions can be relevant in developing an understanding of the mechanism for forming various -sheet structures such as found in many (amyloid-like) neurodegenerative diseases in which protein aggregation is an important pathology. [15][16][17][18] During the past decade, there have been many reports discussing de novo designed, water-soluble -hairpin peptide systems, as well documented in several reviews.…”