Structural highlights
Function
CNEP1_HUMAN Serine/threonine protein phosphatase forming with CNEP1R1 an active phosphatase complex that dephosphorylates and may activate LPIN1 and LPIN2. LPIN1 and LPIN2 are phosphatidate phosphatases that catalyze the conversion of phosphatidic acid to diacylglycerol and control the metabolism of fatty acids at different levels. May indirectly modulate the lipid composition of nuclear and/or endoplasmic reticulum membranes and be required for proper nuclear membrane morphology and/or dynamics. May also indirectly regulate the production of lipid droplets and triacylglycerol. May antagonize BMP signaling.[1] [2] H3BUT5_HUMAN
Publication Abstract from PubMed
C-terminal Domain Nuclear Envelope Phosphatase 1 (CTDNEP1) is a noncanonical protein serine/threonine phosphatase that has a conserved role in regulating ER membrane biogenesis. Inactivating mutations in CTDNEP1 correlate with the development of medulloblastoma, an aggressive childhood cancer. The transmembrane protein Nuclear Envelope Phosphatase 1 Regulatory Subunit 1 (NEP1R1) binds CTDNEP1, but the molecular details by which NEP1R1 regulates CTDNEP1 function are unclear. Here, we find that knockdown of NEP1R1 generates identical phenotypes to reported loss of CTDNEP1 in mammalian cells, establishing CTDNEP1-NEP1R1 as an evolutionarily conserved membrane protein phosphatase complex that restricts ER expansion. Mechanistically, NEP1R1 acts as an activating regulatory subunit that directly binds and increases the phosphatase activity of CTDNEP1. By defining a minimal NEP1R1 domain sufficient to activate CTDNEP1, we determine high-resolution crystal structures of the CTDNEP1-NEP1R1 complex bound to a peptide sequence acting as a pseudosubstrate. Structurally, NEP1R1 engages CTDNEP1 at a site distant from the active site to stabilize and allosterically activate CTDNEP1. Substrate recognition is facilitated by a conserved Arg residue in CTDNEP1 that binds and orients the substrate peptide in the active site. Together, this reveals mechanisms for how NEP1R1 regulates CTDNEP1 and explains how cancer-associated mutations inactivate CTDNEP1.
Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology.,Gao S, Carrasquillo Rodriguez JW, Bahmanyar S, Airola MV Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2321167121. doi: , 10.1073/pnas.2321167121. Epub 2024 May 22. PMID:38776370[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kim Y, Gentry MS, Harris TE, Wiley SE, Lawrence JC Jr, Dixon JE. A conserved phosphatase cascade that regulates nuclear membrane biogenesis. Proc Natl Acad Sci U S A. 2007 Apr 17;104(16):6596-601. PMID:17420445 doi:10.1073/pnas.0702099104
- ↑ Han S, Bahmanyar S, Zhang P, Grishin N, Oegema K, Crooke R, Graham M, Reue K, Dixon JE, Goodman JM. Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway. J Biol Chem. 2012 Jan 27;287(5):3123-37. PMID:22134922 doi:10.1074/jbc.M111.324350
- ↑ Gao S, Carrasquillo Rodríguez JW, Bahmanyar S, Airola MV. Structure and mechanism of the human CTDNEP1-NEP1R1 membrane protein phosphatase complex necessary to maintain ER membrane morphology. Proc Natl Acad Sci U S A. 2024 May 28;121(22):e2321167121. PMID:38776370 doi:10.1073/pnas.2321167121
