Passage of proteins through membranes--old assumptions and new perspectives

This article contains a summary of the ideas that led to the development of the equilibrium theory of protein secretion as an alternative to the current cisternal packaging-exocytosis paradigm. The argument has at its base the philosophical view that the simplest hypothesis should be favored until it is explicity excluded by the weight of evidence. For the transport of molecules across biological membranes this simplest hypothesis is diffusion, and the equilibrium theory simply includes proteins under this rubric. The article then goes on to consider a particular group of experiments that bear on one of three tests of a diffusion mechanism--evidence for the equilibrating nature of the transport process. The evidence that is presented is consistent with a diffusion-based process and does not support secretion by exocytosis. The article then speculates on the potential means by which individual proteins may pass through membranes and focuses on the observed interactions between a digestive enzyme and the membrane phospholipid, phosphatidylinositol. The potential significance of such interactions in the membrane transport of proteins is discussed.