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

Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4081-6. doi: 10.1073/pnas.0914330107. Epub 2010 Feb 16.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Circular Dichroism
  • Hydrogen-Ion Concentration
  • Lipid Bilayers*
  • Membrane Proteins / chemistry*
  • Protein Conformation
  • Protein Folding
  • Spectrometry, Fluorescence
  • Thermodynamics

Substances

  • Lipid Bilayers
  • Membrane Proteins
  • pHLIP protein