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Roles of Carboxyl Groups in the Transmembrane Insertion of Peptides



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doi 10 1016 j jmb 2011 08 010 J Mol Biol 2011 413 359 371 Contents lists available at www sciencedirect com Journal of Molecular Biology j o u r n a l h o m e p a g e h t t p e e s e l s e v i e r c o m j m b Roles of Carboxyl Groups in the Transmembrane Insertion of Peptides Francisco N Barrera 1 Dhammika Weerakkody 2 Michael Anderson 2 Oleg A Andreev 2 Yana K Reshetnyak 2 and Donald M Engelman 1 1 Department of Molecular Biophysics and Biochemistry Yale University PO Box 208114 New Haven CT 06520 USA 2 Physics Department University of Rhode Island Kingston RI 02881 USA Received 6 July 2011 received in revised form 3 August 2011 accepted 5 August 2011 Available online 23 August 2011 Edited by J Bowie Keywords membrane protein folding pHLIP pH trigger carboxyl titration transmembrane helix We have used pHLIP pH low insertion peptide to study the roles of carboxyl groups in transmembrane TM peptide insertion pHLIP binds to the surface of a lipid bilayer as a disordered peptide at neutral pH when the pH is lowered it inserts across the membrane to form a TM helix Peptide insertion is reversed when the pH is raised above the characteristic pKa 6 0 A key event that facilitates membrane insertion is the protonation of aspartic acid Asp and or glutamic acid Glu residues since their negatively charged side chains hinder membrane insertion at neutral pH In order to gain mechanistic understanding we studied the membrane insertion and exit of a series of pHLIP variants where the four Asp residues were sequentially mutated to nonacidic residues including histidine His Our results show that the presence of His residues does not prevent the pHdependent peptide membrane insertion at pH 4 driven by the protonation of carboxyl groups at the inserting end of the peptide A further pH drop leads to the protonation of His residues in the TM part of the peptide which induces peptide exit from the bilayer We also find that the number of ionizable residues that undergo a change in



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