title: Charge pair interactions in transmembrane helices and turn propensity of the connecting sequence promote helical hairpin insertion.
abstract: α-Helical hairpins, consisting of a pair of closely spaced transmembrane (TM) helices that are connected by a short interfacial turn, are the simplest structural motifs found in multi-spanning membrane proteins. In naturally occurring hairpins, the presence of polar residues is common and predicted to complicate membrane insertion. We postulate that the pre-packing process offsets any energetic cost of allocating polar and charged residues within the hydrophobic environment of biological membranes. Consistent with this idea, we provide here experimental evidence demonstrating that helical hairpin insertion into biological membranes can be driven by electrostatic interactions between closely separated, poorly hydrophobic sequences. Additionally, we observe that the integral hairpin can be stabilized by a short loop heavily populated by turn-promoting residues. We conclude that the combined effect of TM-TM electrostatic interactions and tight turns plays an important role in generating the functional architecture of membrane proteins and propose that helical hairpin motifs can be acquired within the context of the Sec61 translocon at the early stages of membrane protein biosynthesis. Taken together, these data further underline the potential complexities involved in accurately predicting TM domains from primary structures.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Universitat de València, E-46100 Burjassot, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bañó-Polo
authors.forename: Luis
authors.initials: L
authors.lastname: Martínez-Gil
authors.forename: Björn
authors.initials: B
authors.lastname: Wallner
authors.forename: José L
authors.initials: JL
authors.lastname: Nieva
authors.forename: Arne
authors.initials: A
authors.lastname: Elofsson
authors.forename: Ismael
authors.initials: I
authors.lastname: Mingarro
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D003198:Computer Simulation; D004591:Electrophoresis, Polyacrylamide Gel; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017955:Poliovirus / Q000235:genetics / Q000378:metabolism; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D014764:Viral Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000596:Amino Acids; D008565:Membrane Proteins; D014764:Viral Proteins