Abstract
We present a conceptual framework for evaluating the effect on the self-association of proteins in membranes due to the presence of other proteins at high concentrations (excluded volume effect) and the high concentration and preoriented state of the reactive species. We have calculated the magnitude of such effects using plausible values for the concentrations of proteins in membranes, for the degree to which proteins may tilt and move vertically, and for their dimensions. Compared to the association of monomers tumbling freely in an experimentally realistic volume, we calculate that these factors alone can increase the likelihood of forming dimers 10(6)-fold and of forming trimers and higher oligomers many orders of magnitude greater. We discuss the implications of our calculations for experimental manipulations of membrane proteins, for biosynthetic assembly of multisubunit membrane proteins and formation of membrane lesions by assemblies of exogenous proteins, and for the activation of cellular events induced by the interaction of membrane receptors with themselves or with other membrane proteins.