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The primary structure of linkers in a new class of modulara-amylases con-stitutes a paradigm of the structural basis that allows a polypeptide to remain nonfolded, extended and pliable. Unfolding is mediated through a depletion of hydrophobic residues and an enrichment of hydrophilic resi-dues, amongst which Ser and Thr are over-represented. | IFEBS Journal How to remain nonfolded and pliable the linkers in modular a-amylases as a case study Georges Feller1 Dominique Dehareng1 and Jean-Luc Da Lage2 1 Center for Protein Engineering University of Liege Liege-Sart Tilman Belgium 2 UPR9034 Evolution Genomes et Speciation CNRS Gif sur Yvette France Keywords glycoside hydrolases intrinsically disordered proteins protein folding protein unfolding a-amylases Correspondence G. Feller Laboratory of Biochemistry Institute of Chemistry B6a B-4000 Liege-Sart Tilman Belgium Fax 32 4 366 33 64 Tel 32 4 366 33 43 E-mail gfeller@ulg.ac.be Received 17 December 2010 revised 18 April 2011 accepted 28 April 2011 doi 10.1111 j.1742-4658.2011.08154.x The primary structure of linkers in a new class of modular a-amylases constitutes a paradigm of the structural basis that allows a polypeptide to remain nonfolded extended and pliable. Unfolding is mediated through a depletion of hydrophobic residues and an enrichment of hydrophilic residues amongst which Ser and Thr are over-represented. An extended and flexible conformation is promoted by the sequential arrangement of Pro and Gly which are the most abundant residues in these linkers. This is complemented by charge repulsion charge clustering and disulfide-bridged loops. Molecular dynamics simulations suggest the existence of conformational transitions resulting from a transient and localized hydrophobic collapse arising from the peculiar composition of the linkers. Accordingly these linkers should not be regarded as fully disordered but rather as possessing various discrete structural patterns allowing them to fulfill their biological function as a free energy reservoir for concerted motions between structured domains. Introduction Following its linear synthesis on the ribosome a polypeptide must adopt its final and biologically active three-dimensional conformation. The forces driving protein folding are essentially based on the hydrophobic effect the entropic cost of encaging
