scholarly journals Navigating the structural landscape of de novo α–helical bundles

2018 ◽  
Author(s):  
Guto G. Rhys ◽  
Christopher W. Wood ◽  
Joseph L. Beesley ◽  
Nathan R. Zaccai ◽  
Antony J. Burton ◽  
...  
Keyword(s):  
De Novo ◽  
Hydrophobic Effect ◽  
Protein Structures ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Single Amino Acid ◽  
Helical Bundles ◽  
Helical Bundle ◽  
Peptide System ◽  
Antiparallel Coiled Coil

ABSTRACTThe association of amphipathic α helices in water leads to α-helical-bundle protein structures. However, the driving force for this—the hydrophobic effect—is not specific and does not define the number or the orientation of helices in the associated state. Rather, this is achieved through deeper sequence-to-structure relationships, which are increasingly being discerned. For example, for one structurally extreme but nevertheless ubiquitous class of bundle—the α-helical coiled coils—relationships have been established that discriminate between all-parallel dimers, trimers and tetramers. Association states above this are known, as are antiparallel and mixed arrangements of the helices. However, these alternative states are less-well understood. Here, we describe a synthetic-peptide system that switches between parallel hexamers and various up-down-up-down tetramers in response to single-amino-acid changes and solution conditions. The main accessible states of each peptide variant are characterized fully in solution and, in most cases, to high-resolution X-ray crystal structures. Analysis and inspection of these structures helps rationalize the different states formed. This navigation of the structural landscape of α-helical coiled coils above the dimers and trimers that dominate in nature has allowed us to design rationally a well-defined and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This robust de novo protein provides another scaffold for further structural and functional designs in protein engineering and synthetic biology.

Guidelines for the assembly of novel coiled-coil structures: α-sheets and α-cylinders

2001 ◽  
Vol 68 ◽  
pp. 111-123 ◽  
Author(s):  
John Walshaw ◽  
Jennifer M. Shipway ◽  
Derek N. Woolfson
Keyword(s):  
Protein Design ◽  
Protein Interactions ◽  
Protein Structures ◽  
Coiled Coil ◽  
Data Bank ◽  
Coiled Coils ◽  
Heptad Repeat ◽  
Protein Protein Interactions ◽  
Helical Bundles ◽  
Heptad Repeats

The coiled coil is a ubiquitous motif that guides many different protein-protein interactions. The accepted hallmark of coiled coils is a seven-residue (heptad) sequence repeat. The positions of this repeat are labelled a-b-c-d-e-f-g, with residues at a and d tending to be hydrophobic. Such sequences form amphipathic α-helices, which assemble into helical bundles via knobs-into-holes interdigitation of residues from neighbouring helices. We wrote an algorithm, SOCKET, to identify this packing in protein structures, and used this to gather a database of coiled-coil structures from the Protein Data Bank. Surprisingly, in addition to commonly accepted structures with a single, contiguous heptad repeat, we identified sequences with multiple, offset heptad repeats. These 'new' sequence patterns help to explain oligomer-state specification in coiled coils. Here we focus on the structural consequences for sequences with two heptad repeats offset by two residues, i.e. a/f′-b/g′-c/a′-d/b′-e/c′-f/d′-g/e′. This sets up two hydrophobic seams on opposite sides of the helix formed. We describe how such helices may combine to bury these hydrophobic surfaces in two different ways and form two distinct structures: open 'α-sheets' and closed 'α-cylinders'. We highlight these with descriptions of natural structures and outline possibilities for protein design.

scholarly journals How coiled-coil assemblies accommodate multiple aromatic residues

2021 ◽  
Author(s):  
Guto G. Rhys ◽  
William M. Dawson ◽  
Joseph L. Beesley ◽  
Freddie J. O. Martin ◽  
R. Leo Brady ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Protein Design ◽  
De Novo ◽  
Complex Structure ◽  
Protein Structures ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Aromatic Residues ◽  
Hydrogen Bond Networks ◽  
Rational Protein Design

ABSTRACTRational protein design requires understanding the contribution of each amino acid to a targeted protein fold. For a subset of protein structures, namely the α;-helical coiled coils (CCs), knowledge is sufficiently advanced to allow the rational de novo design of many structures, including entirely new protein folds. However, current CC design rules center on using aliphatic hydrophobic residues predominantly to drive the folding and assembly of amphipathic α helices. The consequences of using aromatic residues—which would be useful for introducing structural probes, and binding and catalytic functionalities—into these interfaces is not understood. There are specific examples of designed CCs containing such aromatic residues, e.g., phenylalanine-rich sequences, and the use of polar aromatic residues to make buried hydrogen-bond networks. However, it is not known generally if sequences rich in tyrosine can form CCs, or what CC assemblies these would lead to. Here we explore tyrosine-rich sequences in a general CC-forming background and resolve new CC structures. In one of these, an antiparallel tetramer, the tyrosine residues are solvent accessible and pack at the interface between the core and the surface. In the other more-complex structure, the residues are buried and form an extended hydrogen-bond network.

Advanced approaches for the characterization of a de novo designed antiparallel coiled coil peptide

2005 ◽  
Vol 3 (7) ◽  
pp. 1189 ◽  
Author(s):  
Kevin Pagel ◽  
Karsten Seeger ◽  
Bettina Seiwert ◽  
Alessandra VillaCurrent address: J. W. Goethe ◽  
Alan E. Mark ◽  
...  
Keyword(s):  
De Novo ◽  
Coiled Coil ◽  
Antiparallel Coiled Coil

De novo design of α-helical proteins: basic research to medical applications

1996 ◽  
Vol 74 (2) ◽  
pp. 133-154 ◽  
Author(s):  
Robert S. Hodges
Keyword(s):  
Protein Folding ◽  
De Novo ◽  
Coiled Coil ◽  
Basic Research ◽  
De Novo Design ◽  
Coiled Coils ◽  
Medical Applications ◽  
Dimerization Domain ◽  
Recombinant Peptides ◽  
Helical Proteins

The two-stranded α-helical coiled-coil is a universal dimerization domain used by nature in a diverse group of proteins. The simplicity of the coiled-coil structure makes it an ideal model system to use in understanding the fundamentals of protein folding and stability and in testing the principles of de novo design. The issues that must be addressed in the de novo design of coiled-coils for use in research and medical applications are (i) controlling parallel versus antiparallel orientation of the polypeptide chains, (ii) controlling the number of helical strands in the assembly (iii) maximizing stability of homodimers or heterodimers in the shortest possible chain length that may require the engineering of covalent constraints, and (iv) the ability to have selective heterodimerization without homodimerization, which requires a balancing of selectivity versus affinity of the dimerization strands. Examples of our initial inroads in using this de novo design motif in various applications include: heterodimer technology for the detection and purification of recombinant peptides and proteins; a universal dimerization domain for biosensors; a two-stage targeting and delivery system; and coiled-coils as templates for combinatorial helical libraries for basic research and drug discovery and as synthetic carrier molecules. The universality of this dimerization motif in nature suggests an endless number of possibilities for its use in de novo design, limited only by the creativity of peptide–protein engineers.Key words: de novo design of proteins, α-helical coiled-coils, protein folding, protein stability, dimerization domain, dimerization motif.

scholarly journals De novo design of isopeptide bond-tethered triple-stranded coiled coils with exceptional resistance to unfolding and proteolysis: implication for developing antiviral therapeutics

2015 ◽  
Vol 6 (11) ◽  
pp. 6505-6509 ◽  
Author(s):  
Chao Wang ◽  
Wenqing Lai ◽  
Fei Yu ◽  
Tianhong Zhang ◽  
Lu Lu ◽  
...  
Keyword(s):  
De Novo ◽  
Coiled Coil ◽  
De Novo Design ◽  
Coiled Coils ◽  
Isopeptide Bond ◽  
Hiv 1

Isopeptide bridge-tethered ultra-stable coiled-coil trimers have been de novo designed as structure-directing auxiliaries to guide HIV-1 gp41 NHR-peptide trimerization.

scholarly journals Location dependent coordination chemistry and MRI relaxivity, in de novo designed lanthanide coiled coils

2016 ◽  
Vol 7 (3) ◽  
pp. 2207-2216 ◽  
Author(s):  
Matthew R. Berwick ◽  
Louise N. Slope ◽  
Caitlin F. Smith ◽  
Siobhan M. King ◽  
Sarah L. Newton ◽  
...  
Keyword(s):  
Coordination Chemistry ◽  
Binding Site ◽  
De Novo ◽  
Coiled Coil ◽  
Coiled Coils ◽  
Large Impact

Lanthanide binding site translation linearly along a coiled coil has a large impact on stability, coordination chemistry, and MRI relaxivity.

scholarly journals Socket2: A Program for Locating, Visualising, and Analysing Coiled-coil Interfaces in Protein Structures

2021 ◽  
Author(s):  
Prasun Kumar ◽  
Derek N Woolfson
Keyword(s):  
Protein Interactions ◽  
De Novo ◽  
Protein Structures ◽  
Coiled Coil ◽  
Biological Research ◽  
Biological Processes ◽  
Protein Protein Interactions ◽  
Wide Range ◽  
Core Packing ◽  
Natural Amino Acids

Abstract Motivation Protein-protein interactions are central to all biological processes. One frequently observed mode of such interactions is the α-helical coiled coil (CC). Thus, an ability to extract, visualise, and analyse CC interfaces quickly and without expert guidance would facilitate a wide range of biological research. In 2001, we reported Socket, which locates and characterises CCs in protein structures based on the knobs-into-holes (KIH) packing between helices in CCs. Since then, studies of natural and de novo designed CCs have boomed, and the number of CCs in the RCSB PDB has increased rapidly. Therefore, we have updated Socket and made it accessible to expert and non-expert users alike. Results The original Socket only classified CCs with up to 6 helices. Here, we report Socket2, which rectifies this oversight to identify CCs with any number of helices, and KIH interfaces with any of the 20 proteinogenic residues or incorporating non-natural amino acids. In addition, we have developed a new and easy-to-use web server with additional features. These include the use of NGL Viewer for instantly visualising CCs, and tabs for viewing the sequence repeats, helix-packing angles, and core-packing geometries of CCs identified and calculated by Socket2. Availability and implementation Socket2 has been tested on all modern browsers. It can be accessed freely at http://coiledcoils.chm.bris.ac.uk/socket2/home.html. The source code is distributed using an MIT license and available to download under the Downloads tab of the Socket2 home page.

Structure of the N-terminal domain of the effector protein LegC3 fromLegionella pneumophila

2014 ◽  
Vol 70 (2) ◽  
pp. 436-441 ◽  
Author(s):  
Deqiang Yao ◽  
Maia Cherney ◽  
Miroslaw Cygler
Keyword(s):  
Legionella Pneumophila ◽  
Coiled Coil ◽  
Human Cells ◽  
Effector Protein ◽  
Protein Fold ◽  
Sequence Motifs ◽  
Transmembrane Helices ◽  
Helical Bundle ◽  
Terminal Domain ◽  
Antiparallel Coiled Coil

Legionella pneumophilasecretes over 300 effectors during the invasion of human cells. The functions of only a small number of them have been identified. LegC3 is one of the identified effectors, which is believed to act by inhibiting vacuolar fusion. It contains two predicted transmembrane helices that divide the protein into a larger N-terminal domain and a smaller C-terminal domain. The function of LegC3 has been shown to be associated primarily with the N-terminal domain, which contains coiled-coil sequence motifs. The structure of the N-terminal domain has been determined and it is shown that it is highly α-helical and contains a helical bundle followed by a long antiparallel coiled-coil. No similar protein fold has been observed in the PDB. A long loop at the tip of the coiled-coil distal from the membrane is disordered and may be important for interaction with an as yet unidentified protein.

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