Protein acrobatics in pairs--dimerization via domain swapping.

Ever since Anfinsen’s seminal experiments about 50 years ago, it is widely accepted that the amino acid sequence of a protein determines its unique three-dimensional structure. While generally true for single chain proteins, in multimers, two or more individual chains can be assembled in different ways. Therefore, making a distinction between tertiary and quaternary protein structure may be prudent when evoking Anfinsen’s postulate. The folded, native structure of a protein is considered the lowest energy state, with folding being driven by a combination of entropic and enthalpic forces that result in the burial of hydrophobic residues and a specific distribution of polar residues mainly on the surface. This balanced interplay of forces creates a network of defined attractive and repulsive forces that arrange the chain in well-defined, secondary structure elements. The predominance of such cooperative folding on smooth, free energy landscapes for most small, naturally occurring single chain proteins has been explained as the product of natural selection acting at the level of an individual amino acid sequence. When initially established, the protein structure database [1] primarily contained single chain, monomeric proteins; however, over the past several years, the number of multimeric proteins represented in the PDB has increased rapidly and continues to grow. Indeed, multimeric proteins are prevalent in all organisms, and oligomerization is generally believed to be favored during protein evolution [2], since multimers are endowed with structural and functional advantages, such as improved stability and control over the accessibility and specificity of active sites. For multimers, the specification of a unique oligomeric state may not always be unambiguous. Often small changes in protein composition or environment can tip the balance from one arrangement to the next, with some proteins coexisting in more than one oligomeric state. A classic example of alternate oligomers is the Bence-Jones protein, characterized by X-ray diffraction more than 40 years ago. This protein exists in three quaternary structures [3] that vary in their domain interactions. Alternate quaternary assemblies of functionally distinct homo-oligomeric proteins have recently been termed ‘morpheeins’ [4], with the enzyme porphobilinogen synthase (PBGS) as the prototypical example. PBGS exists in an equilibrium between an octamer, a hexamer, and two dimer conformations [5] A special case of oligomer assembly occurs via domain swapping. The term three-dimensional (3D) domain-swapping, or simply domain swapping, was coined by Eisenberg [6] for an oligomerization mechanism in which two or more polypeptide chains exchange identical units. The exchanged portion may consist of a single secondary structure element or an entire globular domain. If exchange is reciprocal between two monomers, dimers are formed, or, if more chains are involved, oligomers ensue (Figure 1). Figure 1 Schematic representation of features inherent to domain swapped structures. Not surprisingly, most domain-swapped structures have been determined by X-ray crystallography. Currently, more than 60 examples of domain swapped structures are available in the PDB [1]. According to the original definition, both monomeric and oligomeric structures must be observed for an identical protein [7], with both states found either in crystals or one in a crystal and the other in solution. This purist’s designation, however, has been relaxed over the last decade. Structures are called domain swapped, even if no structure of the closed monomer has ever been observed or where only a homolog exhibits a closed monomer. Originally, in the former case, the protein is a ‘candidate’ for domain swapping, while in the latter, the oligomers are classified as ‘quasi-domain-swapped’. In the present review, ‘quasi-domain-swapped’ structures are termed domain swapped when the amino acid sequences of monomer and multimer are very similar, i.e. the proteins are mutants or close homologs. The collection of domain swapped protein structures described up to 2002 has been summarized in reviews by Newcomer [8] and Liu and Eisenberg [7]. A more recent review focuses on proteins that display 3D domain swapping as well as fibril formation and discusses the possible involvement of domain swapping in protein deposition diseases [9]. Therefore, I only briefly summarized notations and terminology and the reader is referred to the above reviews for more in depth descriptions of the basic features of domain swapping.