Rice University
Department of Biochemistry and Cell Biology
Kevin R. MacKenzie
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The two stage model of integral membrane protein folding
Stage I: Hydrophobic sequences form stable transbilayer a-helices
The thermodynamic cycle described by Popot and Engelman (1990) identifies the
transmembrane a-helix as the most stable form of a long stretch of apolar
residues that is in the presence of water and a lipid bilayer. The
argument is based on estimates of the free energies for the equilibria described below.
Because the net number of hydrogen bonds is not significantly changed upon going from a helix to a
water-solvated coil,
the
aqueous helix-coil transition is approximately isoenergetic.
Water-lipid partitioning of the helix is estimated to be 30 kcal/mol in favor of the lipid by virtue of
the hydrophobic effect: exposing a hydrophobic helix to water will dramatically reduce water entropy.
The water-lipid partitioning of the coil is estimated to be 40 kcal/mol in
favor of the water due to the loss of protein-water hydrogen bonds upon entering
the bilayer.
The three estimates above suggest that unfolding of an a-helix
within the bilayer is opposed by 70 kcal/mol.
Thus, once a hydrophobic sequence has been inserted into a membrane as a helix, it is
highly unfavorable for that helix to either leave the bilayer or to unfold within the
bilayer.
Stage II: Transbilayer a-helices associate laterally to form bundles
The second part of the two stage model of membrane protein folding consists of
the equilibrium between lipid solvated monomeric a-helices and associations
of the helices into higher order states. The two states of the simplest example
of this equilibrium, monomers and a homodimer, are cartooned below.
The formation of the dimer of helices results in an increase of helix-helix and
lipid-lipid interactions and a loss of helix-lipid interactions. The entropy of
the lipids is expected to increase, as depicted by the blue lipids released upon
dimerization; the entropy of the helices is expected to decrease. The value of
the equilibrium constant will depend on the magnitudes of these entropic terms
and on the enthalpic terms that arise from the detailed helix-helix, helix-lipid,
and lipid-lipid contacts.
Note that helices that form part of polytopic transmembrane proteins may
also be considered to fold in this manner. The association of the hydrophobic
helices into a specific structure is expected to be influenced by the covalent
linkages imposed by extramembraneous loops.
Popot JL and Engelman DM "Membrane protein folding and oligomerization: the
two-stage model" (1990) Biochemistry, 29(17), 4031-7
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