Abstract
In coiled-coil (CC) protein structures α-helices wrap around one another to form rope-like assemblies. Most natural and designed CCs have two–four helices and cyclic (Cn) or dihedral (Dn) symmetry. Increasingly, CCs with five or more helices are being reported. A subset of these higher-order CCs is of interest as they have accessible central channels that can be functionalised; they are α-helical barrels. These extended cavities are surprising given the drive to maximise buried hydrophobic surfaces during protein folding and assembly in water. Here, we show that α-helical barrels can be maintained by the strategic placement of β-branched aliphatic residues lining the lumen. Otherwise, the structures collapse or adjust to give more-complex multi-helix assemblies without Cn or Dn symmetry. Nonetheless, the structural hallmark of CCs—namely, knobs-into-holes packing of side chains between helices—is maintained leading to classes of CCs hitherto unobserved in nature or accessed by design.
Highlights
In coiled-coil (CC) protein structures α-helices wrap around one another to form rope-like assemblies
coiled coils (CCs)-Hept is accessible to chemical synthesis and full biophysical characterisation including X-ray crystallography; it has extended interfaces formed by e = g = Ala; and it is a regular blunt-ended C7-symmetric structure[26]
To understand the diversity of structures formed by the CC-Type[2] peptides, we modelled all of the different sequences onto all of the different structures using ISAMBARD45
Summary
In coiled-coil (CC) protein structures α-helices wrap around one another to form rope-like assemblies. Sequence variations in the heptad repeats discriminate parallel dimers, trimers and tetramers:[10] a = Ile plus d = Leu, directs dimer; a = d = Ile, trimer; and a = Leu plus d = lle, tetramer These preferences reflect differences in KIH packing between oligomers arising from how the Cα–Cβ bond vector of the knob engages with the hole. Structures of natural, engineered and de novo CC assemblies above tetramer are being resolved, including: water-soluble and membrane-spanning CC pentamers;[16,17,18] a 10-helix, viral DNApiloting tube;[19] larger membrane-active pores;[20,21,22] water-soluble CC pentamers–heptamers engineered serendipitously[23,24] or designed computationally;[25,26] and beyond these, there are some more-complex CCs9,15 Many of these have central channels or pores; they are α-helical barrels rather than simpler α-helical bundles[27]. They challenge the primacy of hydrophobicity in determining CC structures, raising the question: what sequences maintain barrels and oppose complete hydrophobic collapse?
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