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

Artykuł
Czasopismo : PLoS Computational Biology   Tom: 10, Zeszyt: 6, Strony: e1003613
Elllinor Haglund [1] , [2] , Joanna Sułkowska [3] , Jeffrey K. Noel [2] , Heiko Lammert [2] , José N. Onuchic [2] , Patricia A. Jennings [4]
  • [1]
    Center for Theoretical Biological Physics (CTBP) and Department of Physics, University of California at San Diego (UCSD), La Jolla, California, United States of America
  • [2]
    Center for Theoretical Biological Physics (CTBP) and Departments of Physics and Astronomy, Chemistry and Biochemistry and Cell Biology, Rice University, Houston, Texas, United States of America
  • [3]
  • [4]
    Departments of Chemistry and Biochemistry, University of California at San Diego (UCSD), La Jolla, California, United States of America
2014-06-19 angielski
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  • Oryginalny artykuł naukowy
  • Zrecenzowana naukowo
Dyscypliny naukowe
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Biofizyka – dziedzina nauk fizycznych
Abstrakty ( angielski )
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A 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 leptin. 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.
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