Pierced Lasso Bundles Are a New Class of Knot-like Motifs

Simple item page
dc.citation.firstpagee1003613en_US
dc.citation.issueNumber6en_US
dc.citation.journalTitlePLoS Computational Biologyen_US
dc.citation.volumeNumber10en_US
dc.contributor.authorHaglund, Ellinoren_US
dc.contributor.authorSulkowska, Joanna I.en_US
dc.contributor.authorNoel, Jeffrey K.en_US
dc.contributor.authorLammert, Heikoen_US
dc.contributor.authorOnuchic, José Nelsonen_US
dc.contributor.authorJennings, Patricia A.en_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2014-07-08T20:19:43Zen_US
dc.date.available2014-07-08T20:19:43Zen_US
dc.date.issued2014en_US
dc.description.abstractA four-helix bundle is a well-characterized motif often used as a target for designed pharmaceutical therapeutics and nutritional supplements. Recently, we discovered a new structural complexity within this motif created by a disulphide bridge in the long-chain helical bundle cytokine epileptic When oxidized, leptin contains a disulphide bridge creating a covalent-loop through which part of the polypeptide chain is threaded (as seen in knotted proteins). We explored whether other proteins contain a similar intriguing knot-like structure as in leptin and discovered 11 structurally homologous proteins in the PDB. We call this new helical family class the Pierced Lasso Bundle (PLB) and the knot-like threaded structural motif a Pierced Lasso (PL). In the current study, we use structure-based simulation to investigate the threading/folding mechanisms for all the PLBs along with three unthreaded homologs as the covalent loop (or lasso) in leptin is important in folding dynamics and activity. We find that the presence of a small covalent loop leads to a mechanism where structural elements slipknot to thread through the covalent loop. Larger loops use a piercing mechanism where the free terminal plugs through the covalent loop. Remarkably, the position of the loop as well as its size influences the native state dynamics, which can impact receptor binding and biological activity. This previously unrecognized complexity of knot-like proteins within the helical bundle family comprises a completely new class within the knot family, and the hidden complexity we unraveled in the PLBs is expected to be found in other protein structures outside the four-helix bundles. The insights gained here provide critical new elements for future investigation of this emerging class of proteins, where function and the energetic landscape can be controlled by hidden topology, and should be take into account in ab initio predictions of newly identified protein targets.en_US
dc.identifier.citationHaglund, Ellinor, Sulkowska, Joanna I., Noel, Jeffrey K., et al.. "Pierced Lasso Bundles Are a New Class of Knot-like Motifs." <i>PLoS Computational Biology,</i> 10, no. 6 (2014) Public Library of Science: e1003613. http://dx.doi.org/10.1371/journal.pcbi.1003613.en_US
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pcbi.1003613en_US
dc.identifier.urihttps://hdl.handle.net/1911/76171en_US
dc.language.isoengen_US
dc.publisherPublic Library of Scienceen_US
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titlePierced Lasso Bundles Are a New Class of Knot-like Motifsen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
journal.pcbi.1003613.pdf
Size:
1.31 MB
Format:
Adobe Portable Document Format
Description:
Download
Collections
Faculty Publications
Biochemistry and Cell Biology Publications
Physics and Astronomy Publications