title: The spontaneous insertion of proteins into and across membranes: the helical hairpin hypothesis.
abstract: We propose that the initial event in the secretion of proteins across membranes and their insertion into membranes is the spontaneous penetration of the hydrophobic portion of the bilayer by a helical hairpin. Energetic considerations of polypeptide structures in a nonpolar, lipid environment compared with an aqueous environment suggest that only alpha and 3(10) helices will be observed in the hydrophobic interior of membranes. Insertion of a polypeptide is accomplished by a hairpin structure composed of two helices, which will partition into membranes if the free energy arising from burying hydrophobic helical surfaces exceeds the free energy "cost" of burying potentially charged and hydrogen-bonding groups. We suggest, for example, that the hydrophobic leader peptide found in secreted proteins and in many membrane proteins forms one of these helices and is oriented in the membrane with its N terminus inside. In secreted proteins, the leader functions by pulling polar portions of a protein into the membrane as the second helix of the hairpin. The occurrence of all categories of membrane proteins can be rationalized by the hydrophobic or hydrophilic character of the two helices of the inserted hairpin and, for some integral membrane proteins, by events in which a single terminal helix is inserted. We propose that, because of the distribution of polar and nonpolar sequences in the polypeptide sequence, secretion and the insertion of membrane proteins are spontaneous processes that do not require the participation of additional specific membrane receptors or transport proteins.
mesh_terms: D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D006860:Hydrogen Bonding; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D011487:Protein Conformation; D011506:Proteins / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008565:Membrane Proteins; D011506:Proteins