Interaction of transmembrane helices by a knobs-into-holes packing characteristic of soluble coiled coils

Abstract

Membrane-embedded protein domains frequently exist as alpha-helical bundles, as exemplified by photosynthetic reaction centers, bacteriorhodopsin, and cytochrome C oxidase. The sidechain packing between their transmembrane helices was investigated by a nearest-neighbor analysis which identified sets of interfacial residues for each analyzed helix-helix interface. For the left-handed helix-helix pairs, the interfacial residues almost exclusively occupy positions a, d, e, or g within a heptad motif (abcdefg) which is repeated two to three times for each interacting helical surface. The connectivity between the interfacial residues of adjacent helices conforms to the knobs-into-holes type of sidechain packing known from soluble coiled coils. These results demonstrate on a quantitative basis that the geometry of sidechain packing is similar for left-handed helix-helix pairs embedded in membranes and coiled coils of soluble proteins. The transmembrane helix-helix interfaces studied are somewhat less compact and regular as compared to soluble coiled coils and tolerate all hydrophobic amino acid types to similar degrees. The results are discussed with respect to previous experimental findings which demonstrate that specific interactions between transmembrane helices are important for membrane protein folding and/or oligomerization.

Modulating Calcitonin Fibrillogenesis

“…Analysis of the primary structure indicates that sCT and LAsCT do have leucine zipper heptad repeats, whereas hCT does not (Scheme 2). In particular, Leu has a high relative occurrence in positions a and d, whereas Tyr and Phe have, respectively, a moderate and low occurrence (38). Furthermore, the b, c, e, f, and g positions correctly contain polar residues.…”

“…Except for Leu 9 , hCT does not show the characteristic heptad repeat at the interior a and d positions occupied by aromatic residues (Scheme 2) whose relative occurrence in coils is low (38). In fact, prediction with COILS indicated that no region of hCT has the potential of forming a coiled-coil.…”

Dimeric structure of transmembrane domain of amyloid precursor protein in micellar environment

“…In the micellar environment, the APPjmtm TM-helices (Lys 699 -Lys 724 ) 2 associate in a left-handed parallel dimer via extended heptad repeat [20] motif I 702 X 3 M 706 X 2 G 709 X 3 A 713 X 2 I 716 X 3 I 720 X 2 I 723 with the distance d between helix axes of 8.3 ± 0.5 Å and the contact surface area of 630 ± 60 Å 2 . In C-terminal part (Gly 709 -Lys 724 ) 2 of the dimer, where spatial structure is determined more precisely, the helix-helix crossing angle h is equal to 26 ± 4°, whereas in the N-terminal part (Lys 699 -Gly 708 ) 2 the h value amounts to 60 ± 11°.…”

How Membranes Shape Protein Structure

“…Tight, knob-into-hole packing has been found to be a general characteristic of helical bundle MPs as well (46,47). For glycophorin A dimerization, knob-into-hole packing is facilitated by the GXXXG motif, in which the glycines permit close approach of the helices.…”