How Membranes Shape Protein Structure*

Constitutive -helical membrane proteins (MPs) are assembled in membranes by means of a translocation/insertion process that involves the translocon complex (1). After release into the membrane’s bilayer fabric, a MP resides stably in a thermodynamic free energy minimum (evidence reviewed in Refs. 2 and 3). This means that the prediction of MP structure from the amino acid sequence is fundamentally a problem of physical chemistry, albeit a complex one. Physical influences that shape MP structure include interactions of the polypeptide chains with water, each other, the bilayer hydrocarbon core, the bilayer interfaces, and cofactors (Fig. 1). Two recent reviews (3, 4) provide extensive discussions of the evolution, structure, and thermodynamic stability of MPs. Here we provide a distilled (and updated) overview that addresses four broad questions. What is the nature of the bilayer matrix that encloses MPs? How can the thermodynamic principles of MP stability be discovered? How does the bilayer matrix induce structure? How can the structure of MPs be predicted? We focus primarily on -helical proteins, but the thermodynamic principles we present also apply to -barrel MPs, which Lukas Tamm discusses elsewhere in this series. Two influences will emerge as paramount in shaping MP structure. First, as implied in Fig. 1, the bilayer fabric of the membrane has two chemically distinct regions: hydrocarbon core (HC) and interfaces (IFs). Interfacial structure and chemistry must be important, because the specificity of protein signaling and targeting by membrane-binding domains could not otherwise exist (5). Second, the high energetic cost of dehydrating the peptide bond, as when transferring it to a non-polar phase, causes it to dominate in the formation of structure (6). The only permissible transmembrane structural motifs of MPs are -helices and -barrels, because internal H-bonding ameliorates this cost.