The Membrane- and Soluble-Protein Helix-Helix Interactome: Similar Geometry via Different Interactions

Abstract

Summary Alpha-helices are a basic unit of protein secondary structure and therefore the interaction between helices is crucial to understanding tertiary and higher-order folds. Comparing subtle variations in the structural and sequence motifs between membrane and soluble proteins sheds light on the different constraints faced by each environment and elucidates the complex puzzle of membrane protein folding. Here, we demonstrate that membrane and water-soluble helix pairs share a small number of similar folds with various interhelical distances. The composition of the residues that pack at the interface between corresponding motifs shows that hydrophobic residues tend to be more enriched in the water-soluble class of structures and small residues in the transmembrane class. The latter group facilitates packing via sidechain- and backbone-mediated hydrogen bonds within the low-dielectric membrane milieu. The helix-helix interactome space, with its associated sequence preferences and accompanied hydrogen-bonding patterns, should be useful for protein structure engineering, prediction and design.

GXXXG‐Mediated Parallel and Antiparallel Dimerization of Transmembrane Helices and Its Inhibition by Cholesterol: Single‐Pair FRET and 2D IR Studies

“…[1][2][3] Because these small residues do not have sufficient side chain hydrophobicities to compensate for the partitioning of the polar main chain of the helix into membranes, [4] the polar surfaces can preferentially pack with each other to avoid lipid exposure. The impact of small residues on transmembrane helix-helix interactions is likely not only of a passive nature, but also involves active forces, such as van der Waals interactions and C α H⋯O=C hydrogen bonds.…”

Toward high-resolution computational design of the structure and function of helical membrane proteins

“…Subsequent analysis based on a much expanded structural database indicated that helical dimer motifs of soluble and membrane proteins share similar geometries, but the membrane motifs are enriched in small amino-acids to facilitate the formation of hydrogen bonds (both side-chain mediated and backbone mediated hydrogen bonds, i.e. Cα–H···O) 22 . This is consistent with the particular importance of hydrogen bonding interactions in establishing tertiary and quaternary structure in membrane proteins 23,24 .…”

Protein structural motifs in prediction and design

“…Several studies have characterized helix-helix associations, showing that they can be described with a small set of structural classes or restricted parameters [23-27]. Grigoryan and Degrado used a generalized set of parameters to describe the structural space of helical bundles [25], showing that coiled coils largely sampled near-ideal parametric structures.…”