Tiny protein coiled coils that self-assemble into cages

Tiny protein coiled coils that self-assemble into cages
CC module structure and CCPO nomenclature. (a) Coiled-coils (CC) are defined by a regular repeating unit of seven amino acid residues, labeled a, b, c, d, e, f, or g (a heptad repeat). Interaction specificity is encoded by hydrophobic interactions at positions a and d (yellow dashed lines) and electrostatic interactions between positions e and g (red dashed lines). DNA complementarity rules are comparatively simple, since only four building elements are present. (b) CC dimers can pair in a parallel or antiparallel orientation. Positions a and d are shown as spheres. B-strand DNA can pair only in an antiparallel orientation. (c) An example name (TET121.10SN-f5) is shown in the middle of the panel. The full names of the polyhedra are defined by the type of polyhedron (TET = tetrahedron; PYR = pyramid; TRIP = trigonal prism) followed by the number of CC segments (show in blue). The subscript (in orange) denotes the topology and circular permutation of each polyhedron, i.e., the double Eulerian path that the polypeptide chain makes over the polyhedron. The next labels (green) denote the type of CC modules used (S = soluble; SN = soluble, negatively charged), linker type (f = flexible; c = charged), and, in subscript form (red), the length of the linker. In cases where two variants have the same name (e.g., different ordering of CC modules), the letters b, c, d, and so forth are appended. The most extensively characterized polyhedra are referred to by shorter names: TET12SN (TET121.10SN-f5), TET12S (TET121.10S-f5), TET12SScr (TET12ScrS-f5), PYR16SN (PYR164.6SN-f5), and TRIP18SN (TRIP187.5RSN-f5). Credit: Nature Biotechnology (2017). DOI: 10.1038/nbt.3994

(Phys.org)—A large team of researchers with members from Slovenia, the U.K, Serbia, France and Spain has developed a technique that causes proteins to self-assemble into geometric shapes on demand. In their paper published in the journal Nature Biotechnology, the group describes their technique and possible uses for the tiny cages.

In recent years, scientists have manipulated DNA strands to cause them to bind together into useful shapes (DNA origami). In this new effort, the researchers have done something similar using proteins instead. Those in the field believe that such objects could be useful for applications like building packets for delivering drugs to targeted locations in the human body.

To cause the proteins to self-assemble, the researchers twisted dual strands of amino acid sections (coiled coils) into amino acid strands that were placed into cut sections of naturally occurring strands. The researchers describe the coiled coils as resembling yarn segments. The sections that were introduced into the chain were chosen specifically because prior testing had shown they would flex in a desired way when exposed to factors like electricity or water. The result was a single strand with bends that caused the overall strand to take the of a geometric object. The team reports that they were able to create tetrahedrons, four-sided pyramids and triangular prisms. Testing of the structures showed them to be soluble in aqueous solutions and that they could take their shapes both inside and outside of cells. The team also showed that the structures could be formed and possibly used in living mice.

The researchers note that parameters such as the charge of the coiled coils and the cap that forms at their ends can be adjusted to create different shapes and for dictating the conditions under which the proteins self-assemble. They further report that it was possible to create a tool-box of building blocks of the structures, allowing for larger, more complex structures from the basic shapes. They suggest such constructs could be used to carry drugs or vaccinations through the body or to create other structures that incorporate amino-acid functionality.

More information: Ajasja Ljubetič et al. Design of coiled-coil protein-origami cages that self-assemble in vitro and in vivo, Nature Biotechnology (2017). DOI: 10.1038/nbt.3994

Abstract
Polypeptides and polynucleotides are natural programmable biopolymers that can self-assemble into complex tertiary structures. We describe a system analogous to designed DNA nanostructures in which protein coiled-coil (CC) dimers serve as building blocks for modular de novo design of polyhedral protein cages that efficiently self-assemble in vitro and in vivo. We produced and characterized >20 single-chain protein cages in three shapes—tetrahedron, four-sided pyramid, and triangular prism—with the largest containing >700 amino-acid residues and measuring 11 nm in diameter. Their stability and folding kinetics were similar to those of natural proteins. Solution small-angle X-ray scattering (SAXS), electron microscopy (EM), and biophysical analysis confirmed agreement of the expressed structures with the designs. We also demonstrated self-assembly of a tetrahedral structure in bacteria, mammalian cells, and mice without evidence of inflammation. A semi-automated computational design platform and a toolbox of CC building modules are provided to enable the design of protein cages in any polyhedral shape.

Journal information: Nature Biotechnology

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