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The use of coiled-coil proteins in drug delivery systems - PubMed

  • ️Thu Jan 01 2009

Review

The use of coiled-coil proteins in drug delivery systems

Ainsley A McFarlane et al. Eur J Pharmacol. 2009.

Abstract

The coiled-coil motif is found in approximately 10% of all protein sequences and is responsible for the oligomerization of proteins in a highly specific manner. Coiled-coil proteins exhibit a large diversity of function (e.g. gene regulation, cell division, membrane fusion, drug extrusion) thus demonstrating the significance of oligomerization in biological systems. The classical coiled-coil domain comprises a series of consecutive heptad repeats in the protein sequence that are readily identifiable by the location of hydrophobic residues at the 'a' and 'd' positions. This gives rise to an alpha-helical structure in which between 2 and 7 helices are wound around each other in the form of a left-handed supercoil. More recently, structures of coiled-coil domains have been solved that have an 11 residue (undecad) or a 15 residue (pentadecad) repeat, which show the formation of a right-handed coiled-coil structure. The high stability of coiled coils, together with the presence of large internal cavities in the pentameric coiled-coil domain of cartilage oligomerization matrix protein (COMPcc) and the tetrameric right-handed coiled coil of Staphylothermus marinus (RHCC) has led us and others to look for therapeutic applications. In this review, we present evidence in support of a vitamin A and vitamin D(3) binding activity for the pentameric COMPcc molecule. In addition, we will discuss exciting new developments which show that the RHCC tetramer is capable of binding the major anticancer drug cisplatin and the ability to fuse it to an antigenic epitope for the development of a new generation of vaccines.

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Figures

Fig. 1
Fig. 1

From α-helices to left- and right-handed coiled coils. In an undistorted α-helix one amino acid residue is rotated 100° along the screw axis and subsequently 3.6 residues are required for a full turn (centre). Coiled coils, which are pairs of α-helices winding around each other, show deviations from this rule. In left-handed coiled coils 7 residues are required for 2 turns and therefore are more tightly wound around each other in a left-handed supercoil to compensate for this missing 20° (left). In contrast, naturally occurring right-handed coiled coils reveal repeats of 11residues per 3 turns or 15 residues per 4 turns of the helix (right). As a consequence they are supercoiled either 20° or 60° to form a right-handed supercoil. Characteristic in all cases are highly repetitive sequence motifs of 7, 11, or 15 amino acid residues (in italics) with conserved aliphatic core residues (underlined) forming the hydrophobic core of coiled-coil channels.

Fig. 2
Fig. 2

Inside and outside forces for coiled coil stabilization. (A) Inside forces are classical "knobs into holes" formations of aliphatic side chains oriented inside the coiled-coil channel. In addition to a and h positioned "knobs into holes" the right-handed coiled coil from Staphylothermus marinus reveals a so far unknown inter-helical hydrophobic core composed of residues in d and e positions (de-layer). (B) In the case of the pentameric COMPcc (PBD-code 1VDF), a ring of five Gln54 residues in position d is arranged to form an inter-helical network of ionic interactions (red dotted lines) and contributes to the binding (green dotted lines) of a chloride ion (highlighted in yellow). (C) Molecular surface model of the tetrameric RHCC structure. Only the front two helices of the RHCC tetramer are shown. Hydrophobic residues are depicted in grey, whereas positively- and negatively-charged residues, which form the major i-i′ + 2 (inter-helical) and i−i + 3 (intra-helical) salt bridges are depicted in blue and red, respectively.

Fig. 3
Fig. 3

Cavities inside tetrameric and pentameric coiled-coil channels. Extraordinary features of COMPcc (A) and RHCC (B) are large cavities along the aliphatic channel core. These cavities (highlighted as yellow van der Waals spheres) can function as storage spaces for a great variety of different cargo systems with large biomedical importance. The volumes of individual cavities are shown in cubic Angstroms (Å3). Salt bridges surrounding individual cavities in RHCC are highlighted in red (acidic resdiues) and blue (basic residues). The Gln54 ring in COMPcc is drawn in colour atom type. Remarkably, both channels allow for different shapes of interior spaces. Whereas RHCC cavities are regularly-arranged separated balls, both cavities in COMPcc are elongated and separated by the Gln54 ring in the d-position.

Fig. 4
Fig. 4

Storage properties of coiled-coil domains. COMPcc has been shown to store vitamin A (A) and vitamin D3 (B). In both cases the elongated cargo is oriented such that its hyroxyl group can form an electrostatic interaction with the Gln54 ring system. In contrast to vitamin A where only molecule is bound, COMPcc can store two vitamin D3 molecules, one in each cavity. (C) The larger cavities in RHCC can store one molecule of cisplatin each. Whereas aliphatic, elongated cargos in COMPcc are diffusing via both N- and C-terminus into the hydrophobic channel, the ionic network in RHCC allows for a diffusion of cisplatin via the inter-helical interface.

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