Human Serine Racemase Weakly Binds the Third PDZ Domain of PSD-95

Area of Science:

• Biochemistry
• Neuroscience
• Structural Biology

Background:

• Human serine racemase (hSR) is a PLP-dependent enzyme crucial for D-serine production, a co-agonist of N-methyl-D-aspartate receptors (NMDARs).
• hSR activity is modulated by various factors, including protein interactions, particularly with postsynaptic density protein 95 (PSD-95), which influences glutamate receptor trafficking.

Purpose of the Study:

• To investigate the structural details and stability of the interaction between human serine racemase (hSR) and the PDZ3 domain of postsynaptic density protein 95 (PSD-95).
• To determine if PSD-95 directly binds and regulates hSR activity in humans.

Main Methods:

• Recombinant human PSD-95 PDZ3 and hSR were used.
• Techniques included glutaraldehyde cross-linking, pull-down assays, isothermal titration calorimetry, nuclear magnetic resonance, and enzymatic assays.

Main Results:

• A weak interaction was detected between human hSR and PSD-95 PDZ3.
• The findings confirm binding between human orthologs but suggest it's insufficient for stable complex formation or regulation.
• Results support the hypothesis that a third protein partner is necessary for PSD-95-mediated regulation of hSR.

Conclusions:

• The direct interaction between hSR and PSD-95 is weak and likely requires additional protein partners, such as stargazin, for functional regulation.
• This study sheds light on the complex regulatory mechanisms of glutamatergic neurotransmission involving hSR and PSD-95.