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Evolution of the Tri-PDZ Domain in PSD95 (DLG-4 Gene)
Riya Nilkant1, Lisa Y Mesrop2, Samuel Lobo3
1Department of Molecular, Cell and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA 93106, USA.
Molecular Biology and Evolution
|December 17, 2025
Summary
The DLG4 gene, encoding the synaptic protein PSD-95, has ancient origins in Filozoa. Its PDZ domains evolved from a single ancestral domain, with hydrogen bonds crucial for PDZ3 ligand interaction.
Area of Science:
- Evolutionary biology
- Molecular biology
- Genomics
Background:
- Synaptic proteins like DLG4 (encoding PSD-95) have ancient origins predating animal life.
- DLG4 is a MAGUK protein with a conserved domain structure including PDZ domains.
Purpose of the Study:
- To trace the evolutionary history of DLG4's tri-PDZ domains to their deep ancestral origin.
- To investigate the conserved binding mechanisms of the PDZ3 domain and its ligand CRIPT.
Main Methods:
- Phylogenetic analysis of DLG4 tri-PDZ domains.
- Evolutionary Scale Modeling (ESM2) for domain conservation.
- AlphaFold2 Multimer for structural and binding analysis.
Main Results:
- DLG4's PDZ domain lineage originated from a single ancestral domain in Filozoa.
- PDZ domain identities are conserved across the animal kingdom boundary.
- CRIPT, a PDZ3 ligand, is conserved in Filozoa, with hydrogen bonds being key to conserved binding.
Conclusions:
- The PDZ domain architecture of DLG4 is ancient and highly conserved.
- Hydrogen bonds represent a foundational innovation for PDZ3-ligand interactions, allowing for broader protein-protein interactions.
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