We have used a series of lipid-associating proteins with similar pI's and with molecular weights between 2280 and 28 000 to study the mechanism of lipid-protein association. All of these polypeptides spontaneously associate with dimyristoylphosphatidylcholine (DMPC) to give quasi-discrete products. The reaction of the apoproteins with unsaturated lecithins is slow, if it occurs at all. Our data support the Kanehisa-Tsong cluster model [Kanehisa & Tsong (1978) J. Am. Chem. Soc. 100, 424] of lipid permeability in many of its qualitative aspects. These are (a) that the rate of lipid-protein association increases with decreasing polypeptide molecular weight, (b) that there is a small temperature dependence for the rate of association of small peptides with DMPC but with large polypeptides the temperature at which association with lipid is rapid is confined to the solid → fluid transition temperature (Tc) of DMPC, and (c) that the rate is asymmetric about Tc, with the change in the rate with respect to temperature below Tc being greater than at T > Tc. In addition, we have shown that unfolded monomeric proteins with a large number of exposed hydrophobic residues associate with DMPC faster than self-associated and/or folded proteins. Our data suggest that the association of some of the apoproteins with phospholipids is subject to kinetic control.
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