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Leucine Motifs Stabilize Residual Helical Structure in Disordered Proteins

Tijdschriftbijdrage - Tijdschriftartikel

Many examples are known of regions of intrinsically disordered proteins that fold into α-helices upon binding to their targets. These helical binding motifs (HBMs) can be partially helical also in the unbound state, and this so-called residual structure can affect binding affinity and kinetics. To investigate the underlying mechanisms governing the formation of residual helical structure, we assembled a dataset of experimental helix contents of 65 peptides containing HBM that fold-upon-binding. The average residual helicity is 17% and increases to 60% upon target binding. The helix contents of residual and target-bound structures do not correlate, however the relative location of helix elements in both states shows a strong overlap. Compared to the general disordered regions, HBMs are enriched in amino acids with high helix preference and these residues are typically involved in target binding, explaining the overlap in helix positions. In particular, we find that leucine residues and leucine motifs in HBMs are the major contributors to helix stabilization and target-binding. For the two model peptides, we show that substitution of leucine motifs to other hydrophobic residues (valine or isoleucine) leads to reduction of residual helicity, supporting the role of leucine as helix stabilizer. From the three hydrophobic residues only leucine can efficiently stabilize residual helical structure. We suggest that the high occurrence of leucine motifs and a general preference for leucine at binding interfaces in HBMs can be explained by its unique ability to stabilize helical elements.

Tijdschrift: J. Mol. Biol.
ISSN: 0022-2836
Issue: 4
Volume: 436
Jaar van publicatie:2024
Trefwoorden:Intrinsically Disordered Proteins/chemistry, Leucine/chemistry, Peptides/chemistry, Protein Structure, Secondary, Amino Acid Motifs, Datasets as Topic, Hydrophobic and Hydrophilic Interactions, Protein Binding, Models, Chemical
Toegankelijkheid:Open