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High-throughput Crystallization of Membrane Proteins Using the Lipidic Bicelle Method
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High-throughput Crystallization of Membrane Proteins Using the Lipidic Bicelle Method

Published on: January 9, 2012

Conformational dimorphism and transmembrane orientation of prion protein residues 110-136 in bicelles

K J Glover1, J A Whiles, M J Wood

  • 1Department of Chemistry and Biochemistry, 0359, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093-0359, USA.

Biochemistry
|October 31, 2001
PubMed

Insights

The prion protein

Area of Science:

  • Biochemistry
  • Structural Biology
  • Neuroscience

Background:

  • The prion protein (PrP) is implicated in neurodegenerative diseases.
  • Understanding PrP's interaction with cell membranes is crucial for disease mechanisms.
  • The membrane-associating domain (residues 110-136) is key to PrP's function.

Purpose of the Study:

  • To investigate the structural behavior of the prion protein's membrane-associating domain (PrP(110-136)).
  • To determine the influence of lipid environment and pH on PrP(110-136) conformation.
  • To elucidate the orientation and insertion of PrP(110-136) within a lipid bilayer.

Main Methods:

  • Phospholipid bicelle model systems.
  • Nuclear Magnetic Resonance (NMR) spectroscopy (amide-lipid NOEs, amide-water chemical exchange).
  • Solid-state deuterium NMR experiments.
  • Site-directed mutagenesis.

Main Results:

  • PrP(110-136) demonstrated pH- and lipid-dependent conformational changes.
  • A transition occurred between an unstructured state at pH 4.5 and an alpha-helical state at pH 7.5.
  • A single histidine residue's charge state was identified as critical for this conformational dimorphism.
  • The helical conformation spanned the lipid bilayer with its axis at a 16° angle to the bilayer normal.

Conclusions:

  • The prion protein's membrane-associating domain exhibits significant conformational plasticity.
  • Lipid interactions and pH are key regulators of PrP(110-136) structure.
  • This domain inserts into the membrane in an alpha-helical conformation, suggesting a mechanism for membrane interaction in disease.

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