Leucine motifs stabilize residual helical structure in disordered proteins

Zavrtanik, Uroš (author), Medved, Tadej (author), Purič, Samo (author), Vranken, Wim F. (author), Lah, Jurij (author), Hadži, San (author)

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.

• Language: English
• Keywords: intrinsically disordered proteins, folding-upon-binding, pre-folding, preotein recognition motif, leucine recognition motif, intrinsic disorder, recognition motif, leucine motif
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2024
• Number of pages: 15 str.
• Numbering: Vol. 436, iss. 4, art. 168444
• PID: 20.500.12556/RUL-155238
• UDC: 577.322
• ISSN on article: 0022-2836
• DOI: 10.1016/j.jmb.2024.168444
• COBISS.SI-ID: 189748995
• Publication date in RUL: 21.03.2024

Record is a part of a journal

• Title: Journal of molecular biology
• Shortened title: J. mol. biol.
• Publisher: Elsevier
• ISSN: 0022-2836
• COBISS.SI-ID: 25766912

Licences

• License: CC BY-NC 4.0, Creative Commons Attribution-NonCommercial 4.0 International
• Link: http://creativecommons.org/licenses/by-nc/4.0/
• Description: A creative commons license that bans commercial use, but the users don’t have to license their derivative works on the same terms.

Secondary language

• Language: Slovenian
• Keywords: intrinzično neurejeni proteini, zvitje ob vezanju, prepoznavni motivi, predzvitje, levcinski prepoznavni motivi