Evolutionary, physicochemical, and functional mechanisms of protein homooligomerization

Abstract

Protein homooligomers afford several important benefits for the cell; they mediate and regulate gene expression, activity of many enzymes, ion channels, receptors, and cell-cell adhesion processes. The evolutionary and physical mechanisms of oligomer formation are very diverse and are not well understood. Certain homooligomeric states may be conserved within protein subfamilies and between different subfamilies, therefore providing the specificity to particular substrates while minimizing interactions with unwanted partners. In addition, transitions between different oligomeric states may regulate protein activity and support the switch between different pathways. In this chapter, we summarize the biological importance of homooligomeric assemblies, physicochemical properties of their interfaces, experimental methods for their identification, their evolution, and role in human diseases.

Figure 1.1

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

Figure 1.2

Distribution of different homooligomeric states in a nonredundant set of Protein Data Bank (PDB) structures (A) and in Eukaryotes, Archaea, and Eubacteria (B). The nonredundant set of structures was obtained using the criteria of BLAST p value <10⁻⁷ on all PDB chains and oligomeric state annotations were taken from PDB.

Figure 1.3

Different 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 of N-acetyl-L-glutamate kinase hexamer (2BUF). Inserted N-terminal helix shown in red enables the hexamer formation. Adapted from Ref. .