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N@a and N@d: Oligomer- and Partner-specification by Asparagine in Coiled-coil Interfaces

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)528–538
Number of pages11
JournalACS Chemical Biology
Volume12
Issue number2
Early online date27 Dec 2016
DOIs
DateAccepted/In press - 27 Dec 2016
DateE-pub ahead of print - 27 Dec 2016
DatePublished (current) - 17 Feb 2017

Abstract

The α-helical coiled coil is one of the best-studied protein-protein interaction motifs. As a result, sequence-to-structure relationships are available for the prediction of natural coiled-coil sequences and the de novo design of new ones. However, coiled coils adopt a wide range of oligomeric states and topologies, and our understanding of the specification of these and the discrimination between them remains incomplete. Gaps in our knowledge assume more importance as coiled coils are used increasingly to construct biomimetic systems of higher complexity; for this, coiled-coil components need to be robust, orthogonal and transferable between contexts. Here we explore how the polar side chain asparagine (Asn, N) is tolerated within otherwise hydrophobic helix-helix interfaces of coiled coils. The long-held view is that Asn placed at certain sites of the coiled-coil sequence repeat selects one oligomer state over others, which is rationalized by the ability of the side chain to make hydrogen bonds, or interactions with chelated ions within the coiled-coil interior of the favored state. We test this with experiments on de novo peptide sequences traditionally considered as directing parallel dimers and trimers; and more widely through bioinformatics analysis of natural coiled-coil sequences and structures. We find that when located centrally, rather than near the termini of such coiled-coil sequences, Asn does exert the anticipated oligomer-specifying influence. However, outside of these bounds, Asn is observed less frequently in the natural sequences, and the synthetic peptides are hyperthermostable and lose oligomer-state specificity. These findings highlight that not all regions of coiled-coil repeat sequences are equivalent, and that care is needed when designing coiled-coil interfaces.

    Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

    Research areas

  • SYNTHETIC BIOLOGY

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the accepted author manuscript (AAM). The final published version (version of record) is available online via American Chemical Society at http://doi.org/10.1021/acschembio.6b00935. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 750 KB, PDF document

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