Caught in self-interaction: evolutionary and functional mechanisms of protein homooligomerization

Abstract

Many soluble and membrane proteins form homooligomeric complexes in a cell which are responsible for the diversity and specificity of many pathways, may mediate and regulate gene expression, activity of enzymes, ion channels, receptors, and cell adhesion processes. The evolutionary and physical mechanisms of oligomerization are very diverse and its general principles have not yet been formulated. Homooligomeric states may be conserved within certain protein subfamilies and might be important in providing specificity to certain substrates while minimizing interactions with other unwanted partners. Moreover, recent studies have led to a greater awareness that transitions between different oligomeric states may regulate protein activity and provide the switch between different pathways. In this paper we summarize the biological importance of homooligomeric assemblies, physico-chemical properties of their interfaces, experimental and computational methods for their identification and prediction. We particularly focus on homooligomer evolution and describe the mechanisms to develop new specificities through the formation of different homooligomeric complexes. Finally, we discuss the possible role of oligomeric transitions in the regulation of protein activity and compile a set of experimental examples with such regulatory mechanisms.

Figure 1. Distribution of homooligomeric states in a non-redundant set of Protein Data Bank (PDB) structures

The non-redundant set was obtained using the criteria of BLAST p-value < 10e-07 on all PDB chains and oligomeric states were annotated by PISA [20].

Figure 2. Mechanisms of homooligomerization

A. Domain swapping of RNase A: monomer (1RTB) and domain-swapped dimer (1A2W) of RNase A. The swapped regions and domain linker regions are shown as red and yellow, respectively. B. Leu-zipper of GCN4 (1YSA). Leu at position “d” is shown as stick model and colored in red. C. amino acid substitutions for designed homooctamer of L-rhamnulose-1-phosphatase aldolase (2UYU). The original protein exists as a tetramer which is shifted to the octamer upon a single substitution (A88F, shown in red). D. Insertions and deletions of N-acetyl-L-glutamate kinase hexamer (2BUF). Inserted N-terminal helix shown in red enables the hexamer formation.

Figure 3

Illustration for the development of novel protein specificities and regulation of protein activity through homooligomerization.