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Review
, 11 (6), 1285-99

3D Domain Swapping: As Domains Continue to Swap

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Review

3D Domain Swapping: As Domains Continue to Swap

Yanshun Liu et al. Protein Sci.

Abstract

Three-dimensional (3D) domain swapping creates a bond between two or more protein molecules as they exchange their identical domains. Since the term '3D domain swapping' was first used to describe the dimeric structure of diphtheria toxin, the database of domain-swapped proteins has greatly expanded. Analyses of the now about 40 structurally characterized cases of domain-swapped proteins reveal that most swapped domains are at either the N or C terminus and that the swapped domains are diverse in their primary and secondary structures. In addition to tabulating domain-swapped proteins, we describe in detail several examples of 3D domain swapping which show the swapping of more than one domain in a protein, the structural evidence for 3D domain swapping in amyloid proteins, and the flexibility of hinge loops. We also discuss the physiological relevance of 3D domain swapping and a possible mechanism for 3D domain swapping. The present state of knowledge leads us to suggest that 3D domain swapping can occur under appropriate conditions in any protein with an unconstrained terminus. As domains continue to swap, this review attempts not only a summary of the known domain-swapped proteins, but also a framework for understanding future findings of 3D domain swapping.

Figures

Fig. 1.
Fig. 1.
Schematic diagram illustrating terms related to 3D domain swapping. The swapped domain in an oligomer is a globular domain or a structural element of one subunit that extends into another subunit and interacts with the main domain of this subunit. This interaction is essentially identical to that of the same domain in the monomer. The hinge loop is a segment of polypeptide chain that links the swapped domain and the main domain. This loop adopts different conformations in the monomer and the domain-swapped oligomer. The closed interface is the interface between the swapped domain and the main domain that exists in both the monomer and the domain-swapped oligomer. The open interface exists only in the domain-swapped oligomer, but not in the monomer. The functional unit is shown in the dashed box. Its swapped domain and main domain are from different polypeptide chains. Under certain circumstances, a conformational change in the hinge loop converts a closed monomer to an open monomer with its closed interface exposed to the solvent. Two or more such open monomers form a domain-swapped dimer or oligomer. Domain-swapped oligomers are divided into two types: open oligomers and closed oligomers. The open oligomer is linear and has one closed interface exposed to solvent, whereas the closed oligomer is cyclic and does not expose a closed interface.
Fig. 2.
Fig. 2.
Ribbon diagrams of the structures of the RNase A monomer (2.0 Å, Wlodawer et al. 1982), the N-terminal swapped dimer (2.1 Å, Liu et al. 1998), the C-terminal swapped dimer (1.75 Å, Liu et al. 2001), the N- and C-terminal swapped trimer model (Liu et al. 2001), and the cyclic C-terminal swapped trimer (2.2 Å, Liu et al. 2002). The N- and C-termini are labeled. The N-terminal helix and the C-terminal strand that are swapped in the oligomers are colored blue and red, respectively, in the monomer. The N-terminal swapped dimer swaps its N-terminal helix, whereas the C-terminal swapped dimer swaps its C-terminal strand. Both types of swapping take place in the N- and C-terminal swapped trimer model: The green subunit swaps its C-terminal strand with the red subunit, and swaps its N-terminal helix with the blue subunit. The cyclic C-terminal swapped trimer is 3D domain-swapped at its three C-terminal strands. The three subunits of the molecule are related by a three-fold axis, giving the molecule the shape of a propeller. The figure was created using Raster 3D (Merritt and Bacon 1997).
Fig. 3.
Fig. 3.
Ribbon representations of hypothetical models of RNase A tetramers. RNase A is known to form tetramers, but their structures are unknown. These models are based on the structures of the RNase A minor dimer, major dimer, and minor trimer. (A) A tetramer model with two C-terminal strands swapped and one N-terminal helix swapped. (B) A tetramer model with one C-terminal strand swapped and two N-terminal helices swapped. (C) A tetramer model with a combination of cyclic and linear oligomerization. In this model, three subunits form a cyclic trimer by swapping the C-terminal strand. One of these three subunits swaps its N-terminal helix with the fourth subunit. This mode of domain swapping can lead to branching chains. (D) A cyclic tetramer model with the swapping of four C-terminal strands. The figure was created with Raster3D (Merritt and Bacon 1997).
Fig. 4.
Fig. 4.
Ribbon diagram of the structure of blood coagulant factor IX/X-bp (Mizuno et al. 1997). IX/X-bp is a heterodimer, with subunit A in red and subunit B in green. The N- and C-termini are indicated. The middle loops of the two subunits are swapped. IX/X-bp is the first example of 3D domain swapping of a heterodimer and with the central part of the molecule swapped. The figure was created with Raster3D (Merritt and Bacon 1997).
Fig. 5.
Fig. 5.
Ribbon diagram of the structure of human glyoxalase I (Cameron et al. 1997). Glyoxalase I is a homodimer, shown with one subunit colored red and one green. The N-and C-termini are labeled. The N-terminal helix is swapped (shown by the arrowheads on the dashed line). There are two ways to define the monomer. In one way, the monomer is composed of the domains in the pink- and blue-shaded areas. These two globular domains of the monomer are from the same polypeptide chain (red or green), and therefore, the C-terminal domain is not swapped. In the second way, the monomer is composed of the domains in the blue- and gray-shaded areas. To obtain such a monomer, the domain in the gray-shaded area must be replaced by the domain in the blue-shaded area in the crystal structure, as shown by the arrowheads on the solid line. Then the C-terminal domain is considered to be swapped, and therefore there are two swapped domains in this case. The figure was created with Raster3D (Merritt and Bacon 1997).
Fig. 6.
Fig. 6.
An open oligomeric domain-swapped structure, illustrated by a ribbon diagram of the structure of T7 helicase 4E fragment (Sawaya et al. 1999). The hexamer of T7 helicase 4E has a six-fold screw axis in the molecule, which is coincident with the crystallographic symmetry. 3D domain swapping is displayed along the screw axis throughout the crystal. (A) A view of the hexamer along the screw axis. (B) A view of the hexamer perpendicular to the screw axis. The figure was created with Raster3D (Merritt and Bacon 1997).

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