Human Serine Racemase Weakly Binds the Third PDZ Domain of PSD-95 |
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| Authors: | Roberta Giaccari Francesco Marchesani Carlotta Compari Emilia Fisicaro Andrea Mozzarelli Barbara Campanini Stefano Bettati Stefano Bruno Serena Faggiano |
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| Affiliation: | 1.Department of Food and Drug, University of Parma, 43124 Parma, Italy; (R.G.); (F.M.); (C.C.); (E.F.); (A.M.); (B.C.); (S.B.);2.Institute of Biophysics, CNR, 56124 Pisa, Italy;3.Biopharmanet TEC, University of Parma, 43124 Parma, Italy;4.Department of Medicine and Surgery, University of Parma, 43124 Parma, Italy |
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| Abstract: | Human serine racemase (hSR) is a pyridoxal-5′-phosphate (PLP)-dependent dimer that catalyzes the formation of D-serine from L-serine, as well as the dehydration of both L- and D-serine to pyruvate and ammonia. As D-serine is a co-agonist of N-methyl-D-aspartate receptors (NMDARs), hSR is a key enzyme in glutamatergic neurotransmission. hSR activity is finely regulated by Mg2+, ATP, post-translational modifications, and the interaction with protein partners. In particular, the C-terminus of murine SR binds the third PDZ domain (PDZ3) of postsynaptic density protein 95 (PSD-95), a member of the membrane-associated guanylate kinase (MAGUK) family involved in the trafficking and localization of glutamate receptors. The structural details of the interaction and the stability of the complex have not been elucidated yet. We evaluated the binding of recombinant human PSD-95 PDZ3 to hSR by glutaraldehyde cross-linking, pull-down assays, isothermal titration calorimetry, nuclear magnetic resonance, and enzymatic assays. Overall, a weak interaction was observed, confirming the binding for the human orthologs but supporting the hypothesis that a third protein partner (i.e., stargazin) is required for the regulation of hSR activity by PSD-95 and to stabilize their interaction. |
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| Keywords: | serine racemase D-serine PDZ domain PSD-95 SAP-90 DLG4 protein– protein interaction N-methyl-D-aspartate receptor |
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