Molten globules lure transmembrane helices away from the membrane

Thanks to the rapid progress in membrane protein crystallography and cryogenic electron microscopy in recent years, we have become increasingly accustomed to seeing protein structures characterized by long transmembrane α-helices (TMHs) crisscrossing a lipid bilayer (1). But how is it decided which segments of the polypeptide form the TMHs, and what are the precise sequence requirements for their membrane insertion? The great majority of integral membrane proteins require one or another type of translocon to catalyze insertion into the target membrane. The most commonly used and best understood of these are the universally conserved Sec-type translocons found in the cytoplasmic membrane of bacteria (the SecYEG complex) and the endoplasmic reticulum (ER) membrane in eukaryotes (the Sec61 complex) (2). They mediate cotranslational membrane insertion of the growing polypeptide as it emerges from the exit tunnel of translocon-bound ribosomes (3), and have an evolutionary conserved structure with a central channel through which hydrophilic polypeptide segments can be translocated across the membrane and a dynamic “lateral gate” through which hydrophobic segments in the nascent polypeptide chain can partition into the surrounding lipid bilayer to form TMHs (4, 5). Over the past two decades, statistical and experimental studies have progressively uncovered the sequence characteristics that define the difference between polypeptide segments that can form TMHs and those that cannot. To a first approximation, the efficiency of membrane insertion of a TMH is dictated by its hydrophobicity, although interactions with neighboring TMHs, or sequence variations in segments immediately flanking the TMH, can shift the hydrophobicity threshold (HT) required for … [↵][1]1Email: gunnar{at}dbb.su.se. [1]: #xref-corresp-1-1