New currency for old rope: from coiled-coil assemblies to α-helical barrels
Highlights
► α-Helical coiled coils are ubiquitous protein–protein-interaction domains. ► Dimers, trimers and tetramers dominate, but more-complex assemblies are possible. ► Understanding sequence-to-structure relationships for these states is improving. ► Pentamers and above are barrel-like with central channels or pores. ► Recent studies show that de novo hexamers that can be internally functionalised.
Section snippets
Introduction: backdrop to and outlook for this review
The concept of the α-helical coiled-coil protein structure—that is, two or more helices wrapped around each other to form consolidated rope-like assemblies—has been with us for nearly 60 years [1, 2], experimental validations of this for over a quarter of a century [3, 4, 5], and the rational engineering and design of such structures has been finessed considerably over the past two decades [6, 7]. By any measure, coiled-coil structural biology constitutes a mature research field. Nevertheless,
Basics of coiled-coil sequence, structure and function
α-Helical coiled coils constitute on average 3% of all protein-encoding regions of the known genomes [16]. They were first recognised in certain classes of fibrous protein, and, possibly as a result of this, their primary role has mainly been considered as structural. Indeed, coiled-coil domains are largely associated with directing, specifying and cementing protein–protein interactions. However, they play oligomerisation and structural roles in virtually all intracellular and extracellular
Knobs-into-holes packing and sharper sequence-to-structure relationships
Of course, there must be more to sequence-to-structure relationships in coiled coils to account for the large proportion of such sequences in the known genomes, the complexity of structures that they form, and the presumed necessity for these to be orthogonal, that is, non-promiscuous. The key to understanding this lies in the knobs-into-holes (KIH) interactions first postulated by Crick [1]. Side chains from adjacent helices in coiled-coil structures do not simply contact each other, rather
New analysis, database, prediction and modelling tools for coiled-coil structure
Thankfully, coiled-coil structures do not have to be inspected by eye to uncover their secrets. Two programs in particular garner many of the important parameters of coiled-coil geometry. TWISTER [35] and SOCKET [19] identify important structural features from 3D coordinates of coiled-coil structures, such as those deposited in the RCSB Protein Data Bank (PDB) [36]. Whilst TWISTER calculates backbone and related parameters for coiled-coil geometries, SOCKET identifies runs of KIH interactions
Extended KIH packing and the potential for higher-order states
Another consequence of increasing oligomer state is that residues other than those at a and d become more involved in the helix-helix interfaces, Figure 2c, d. Specifically, the e and g sites become progressively buried. The extreme is that residues at these positions become knobs, and part of what have been termed peripheral KIH interactions [50]. These trends can be seen through SOCKET analyses of the GCN4 variants, the Basis-set peptides and natural coiled coils. The natural extremes are
New higher-order assemblies, a coiled-coil hexamer (CC-Hex)
Considering these possibilities of offset double-heptad repeats opens up a whole new space in coiled-coil assembly that is just beginning to be realised and explored. For example, recently, the Basis-set tetramer, CC-Tet, has been used to create a parallel coiled-coil hexamer, CC-Hex [8••]. The details of this study are illuminating. First, CC-Tet has a traditional N-type heptad repeat that specifies tetramer using the Harbury relationships, that is (ELAAIKX)4. The X-ray structure reveals a
Towards α-helical barrels
CC-Hex raises the bar of oligomer states accessible to coiled-coil motifs. So how far can the concept of extended KIH patterns be pushed to model, predict and design new coiled-coil oligomers? CC-Hex is a true and classical coiled coil; that is, it has a contiguous ring of KIH interactions, albeit surrounding an internal channel. There is heptameric coiled coil in the CC+ database—a mutant of GCN4-p1 with g = e = Ala [28]—however we note that this is far from a classical coiled coil: the SOCKET
Conclusions: prospects for the future discoveries and designs
The leap from 6-membered and 7-membered barrels to those with 12 helices raises the questions: are true coiled-coil octomers, nonomers, decamers and hendecamers possible, and what about oligomers above that? If any of these were to be observed in nature, or could be designed de novo, they would not only be of interest in coiled-coil ‘stamp collecting’, but could have an impact in the design of ion-channels, binding proteins, sensors and even enzymes [8••, 61]. To illustrate this potential, an
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank the Woolfson group, Leo Brady, Vince Conticello, Stuart Conway, Noah Linden and Richard Sessions for helpful discussions, and the BBSRC and EPSRC of the UK for funding (grant numbers: BB/G008833/1 and EP/J01430/1).
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