Evolutionary Expansion and Specialization of the PDZ Domains

Abstract

PDZ domains are protein-protein interaction modules widely used to assemble membranous signaling complexes including those found in the neuronal synapse. PDZ-containing genes encoded in metazoan genomes vastly outnumber those in prokaryotes, plants, and fungi. By comparing 40 proteomes to track the evolutionary history of the PDZ domain, we observed that the variety of associations between PDZ and other domains expands greatly along the stem leading to metazoans and choanoflagellates. We asked whether the expansion of PDZ domains was due to random or specific sequence changes. Studying the sequence signatures of 58 PDZ lineages that are common to bilaterian animals, we showed that six common amino acid residues are able to classify 96% of PDZ domains to their correct evolutionary lineage. In PDZ domain-ligand cocrystals, four of these "classifying positions" lie in direct contact with the -1 and -3 residues of the ligand. This suggests coevolution of the more flexible regions of the binding interaction as a central mechanism of specialization inherent within the PDZ domain. To identify these positions, we devised two independent algorithms--a metric termed within-clade entropy (WCE) and an average mutual information (AvgMI) score--that both reached similar results. Extending these tools to the choanoflagellate, Monosiga brevicollis, we compared its PDZ domains with their putative metazoan orthologs. Interestingly, the M. brevicollis genes lack conservation at the classifying positions suggesting dissociation between domain organization in multidomain proteins and specific changes within the PDZ domain.

The Role of Backbone Hydrogen Bonds in the Transition State for Protein Folding of a PDZ Domain

“…It is reasonable that the ligand-binding groove of PDZ domains, which is optimized for function, should not affect the folding pathway, since this could lead to misfolding. Thus, while other parts of the PDZ domain govern early events in the folding reaction of PDZ domains [16]–[18], the ligand-binding groove may accept thermodynamically unfavourable amino acid side-chains, such as the conserved His in α2 [16], [36], allowing for evolution of new specificities [37], [38].…”

Comparative genomic analysis of SET domain family reveals the origin, expansion, and putative function of the arthropod-specific SmydA genes as histone modifiers in insects

“…Domain duplication can be achieved via frequent domain-containing gene family expansion. Thus, the member number of a gene family that contains domains can be expanded, representing a common method by which divergence to domain sequences can lead to the evolutionary novelty of domain-containing genes [3]. Rapid domain diversification in particular lineages is important for the adaptation of lineage-specific ecological specializations [4].…”

Physiology and Evolution of Voltage-Gated Calcium Channels in Early Diverging Animal Phyla: Cnidaria, Placozoa, Porifera and Ctenophora

“…Interestingly, cnidarian proteomes also have more PDZ protein-protein interaction motifs compared to pre-metazoans and more early-diverging animals, and less than bilaterian animals which possess more complex nervous systems. This is notable because PDZ motifs play important roles in synaptic protein scaffolding, and their expansion might have contributed to synapse evolution and complexification (Sakarya et al, 2010). …”