The evolution of non-motif selectivity determinants in Monosiga brevicollis PDZ domains [article]

Melody Gao, Iain G.P. Mackley, Samaneh Mesbahi-Vasey, Haley A. Bamonte, Sarah A. Struyvenberg, Louisa Landolt, Nick J. Pederson, Lucy I. Williams, Christopher D. Bahl, Lionel Brooks, Jeanine F. Amacher
2020 bioRxiv   pre-print
The evolution of signaling pathways is complex and well-studied. In particular, the emergence of animal multicellularity had a major impact on protein-protein interactions and signaling systems in eukaryotic cells. However, choanoflagellates, our closest non-metazoan ancestor, contain a number of closely related signaling and trafficking proteins and domains. In addition, because choanoflagellates can adopt a rosette-/multicellular-like state, a lot can be gained by comparing proteins involved
more » ... proteins involved in choanoflagellate and human signaling pathways. Here, we look at how selectivity determinants evolved in the PDZ domain. There are over 250 PDZ domains in the human proteome, which are involved in critical protein-protein interactions that result in large multimolecular complexes, e.g., in the postsynaptic density of neuronal synapses. Binding of C-terminal sequences by PDZ domains is often transient and recognition typically involves 6 residues or less, with only 2 residues specifying the binding motif. We solved high resolution crystal structures of Monosiga brevicollis PDZ domains homologous to human Dlg1 PDZ2, Dlg1 PDZ3, GIPC, and SHANK1 PDZ domains to investigate if the non-motif preferences are conserved, despite hundreds of millions of years of evolution. We also calculated binding affinities for GIPC, SHANK1, and SNX27 PDZ domains from M. brevicollis. Overall, we found that peptide selectivity is conserved between these two disparate organisms, with one exception, mbDLG-3. In addition, we identify 178 PDZ domains in the M. brevicollis proteome, including 11 new sequences, which we verified using Rosetta and homology modeling. Overall, our results provide novel insight into signaling pathways in the choanoflagellate organism.
doi:10.1101/2020.05.28.121053 fatcat:6cdcgleyrjg4zf3p2kzolkmxny