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PH (low) insertion peptide (pHLIP) inserts across a lipid bilayer as a helix and exits by a different path.


ABSTRACT: What are the molecular events that occur when a peptide inserts across a membrane or exits from it? Using the pH-triggered insertion of the pH low insertion peptide to enable kinetic analysis, we show that insertion occurs in several steps, with rapid (0.1 sec) interfacial helix formation, followed by a much slower (100 sec) insertion pathway to give a transmembrane helix. The reverse process of unfolding and peptide exit from the bilayer core, which can be induced by a rapid rise of the pH from acidic to basic, proceeds approximately 400 times faster than folding/insertion and through different intermediate states. In the exit pathway, the helix-coil transition is initiated while the polypeptide is still inside the membrane. The peptide starts to exit when about 30% of the helix is unfolded, and continues a rapid exit as it unfolds inside the membrane. These insights may guide understanding of membrane protein folding/unfolding and the design of medically useful peptides for imaging and drug delivery.

SUBMITTER: Andreev OA 

PROVIDER: S-EPMC2840156 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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pH (low) insertion peptide (pHLIP) inserts across a lipid bilayer as a helix and exits by a different path.

Andreev Oleg A OA   Karabadzhak Alexander G AG   Weerakkody Dhammika D   Andreev Gregory O GO   Engelman Donald M DM   Reshetnyak Yana K YK  

Proceedings of the National Academy of Sciences of the United States of America 20100216 9


What are the molecular events that occur when a peptide inserts across a membrane or exits from it? Using the pH-triggered insertion of the pH low insertion peptide to enable kinetic analysis, we show that insertion occurs in several steps, with rapid (0.1 sec) interfacial helix formation, followed by a much slower (100 sec) insertion pathway to give a transmembrane helix. The reverse process of unfolding and peptide exit from the bilayer core, which can be induced by a rapid rise of the pH from  ...[more]

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