| First Author | Numagami Y | Year | 2023 |
| Journal | Biochim Biophys Acta Mol Cell Biol Lipids | Volume | 1868 |
| Issue | 3 | Pages | 159265 |
| PubMed ID | 36528254 | Mgi Jnum | J:349831 |
| Mgi Id | MGI:7413720 | Doi | 10.1016/j.bbalip.2022.159265 |
| Citation | Numagami Y, et al. (2022) Distinct regions of Praja-1 E3 ubiquitin-protein ligase selectively bind to docosahexaenoic acid-containing phosphatidic acid and diacylglycerol kinase delta. Biochim Biophys Acta Mol Cell Biol Lipids 1868(3):159265 |
| abstractText | 1-Stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA) interacts with and activates Praja-1 E3 ubiquitin-protein ligase (full length: 615 aa) to ubiquitinate and degrade the serotonin transporter (SERT). SERT modulates serotonergic system activity and is a therapeutic target for depression, autism, obsessive-compulsive disorder, schizophrenia and Alzheimer's disease. Moreover, diacylglycerol kinase (DGK) delta2 (full length: 1214 aa) interacts with Praja-1 in addition to SERT and generates 18:0/22:6-PA, which binds and activates Praja-1. In the present study, we investigated the interaction of Praja-1 with 18:0/22:6-PA and DGKdelta2 in more detail. We first found that the N-terminal one-third region (aa 1-224) of Praja-1 bound to 18:0/22:6-PA and that Lys141 in the region was critical for binding to 18:0/22:6-PA. In contrast, the C-terminal catalytic domain of Praja-1 (aa 446-615) interacted with DGKdelta2. Additionally, the N-terminal half of the catalytic domain (aa 309-466) of DGKdelta2 intensely bound to Praja-1. Moreover, the N-terminal region containing the pleckstrin homology and C1 domains (aa 1-308) and the C-terminal half of the catalytic domain (aa 762-939) of DGKdelta2 weakly associated with Praja-1. Taken together, these results reveal new functions of the N-terminal (aa 1-224) and C-terminal (aa 446-615) regions of Praja-1 and the N-terminal half of the catalytic region (aa 309-466) of DGKdelta2 as regulatory domains. Moreover, it is likely that the DGKdelta2-Praja-1-SERT heterotrimer proximally arranges the 18:0/22:6-PA-producing catalytic domain of DGKdelta2, the 18:0/22:6-PA-binding regulatory domain of Praja-1, the ubiquitin-protein ligase catalytic domain of Praja-1 and the ubiquitination acceptor site-containing SERT C-terminal region. |
