Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on curation of immunofluorescence data
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
ORMDL proteins are a conserved new family of endoplasmic reticulum membrane proteins.
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ORMDL3 encodes a 153 amino acid ER-resident transmembrane protein. GFP-ORMDL3 colocalizes with ER marker PDI but not with plasma membrane marker concanavalin A in COS-7 cells. Human ORMDL3 can rescue yeast orm1/orm2 double knockout phenotypes, demonstrating functional conservation.
"Confocal scanning microscopy using an antibody against protein-disulfide isomerase (PDI), an ER-marker protein, showed an overlapping signal in the endoplasmic reticulum"
Orm family proteins mediate sphingolipid homeostasis.
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Landmark study identifying ORM/ORMDL proteins as negative regulators of SPT that form a conserved complex (SPOTS complex) with SPT and Sac1. ORMDL3 co-immunoprecipitates with SPTLC1 in human HEK293T cells. Triple RNAi knockdown of ORMDL1/2/3 in HeLa cells increases ceramide levels ~3-fold.
"we found that simultaneous knock-down by RNAi of ORMDL1/2/3 in Hela cells causes an approximately three-fold increase in ceramide levels"
ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis.
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ORMDLs and SPT form stable complexes in human cells. ORMDL is normally expressed in functional excess relative to SPT, meaning ORMDL3 overexpression does not further suppress biosynthesis. The relationship between ORMDL3 expression and sphingolipid levels is complex and stoichiometry-dependent.
"We determined that ORMDL is expressed in functional excess relative to SPT at normal levels of expression. ORMDLs and SPT form stable complexes that are not increased by elevated ORMDL3 expression."
ORMDL3 Facilitates the Survival of Splenic B Cells via an ATF6α-Endoplasmic Reticulum Stress-Beclin1 Autophagy Regulatory Pathway.
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ORMDL3 knockout in mice decreases mature B cells, increases splenic B cell apoptosis, and reduces autophagy. ORMDL3 promotes B cell survival via ATF6-Beclin1 autophagy pathway. These are likely downstream effects of altered sphingolipid metabolism and ER stress.
"silencing Ormdl3 in vivo significantly decreased the proportions of mature B lymphocytes and transitional 2B cells in spleen"
A reference map of the human binary protein interactome.
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High-throughput binary protein interactome mapping study (HuRI). Reports many ORMDL3 interactors but most are unvalidated membrane protein interactions from yeast two-hybrid screens.
"Here we present a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'. With approximately 53,000 protein-protein interactions"
Structural insights into the regulation of human serine palmitoyltransferase complexes.
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Cryo-EM structures of the human SPT-ORMDL3 complex at 2.6-3.4 Angstrom resolution. Reveals that ORMDL3 blocks the SPT substrate-binding tunnel through its N-terminus, competing with substrate binding. ssSPTa shapes the tunnel to determine substrate specificity.
"ORMDL3 blocks the tunnel and competes with substrate binding through its amino terminus"
Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex.
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Independent cryo-EM structures of the human SPT-ORMDL3 complex at 3.2 Angstrom resolution confirming the four-transmembrane topology of ORMDL3 and its integration within the SPT holoenzyme.
"ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly"
Ceramide sensing by human SPT-ORMDL complex for establishing sphingolipid homeostasis.
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Cryo-EM structures and mutagenesis demonstrating that ceramide binds to the ORMDL3 N-terminus and stabilizes the inhibitory conformation that blocks SPT activity. Key residue Asn13 is essential for ceramide sensing.
"Structural studies indicate that ceramide can induce and lock the N-terminus of ORMDL3 into an inhibitory conformation."
The ORMDL/Orm-serine palmitoyltransferase (SPT) complex is directly regulated by ceramide: Reconstitution of SPT regulation in isolated membranes.
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Reconstitution of SPT regulation in isolated membranes demonstrates that ceramide directly regulates the ORMDL/SPT complex, providing biochemical evidence for the ceramide feedback mechanism.
"Sphingolipid and ORMDL-dependent regulation of SPT was demonstrated in isolated membranes, essentially free of cytosol. This suggests that this regulation does not require soluble cytosolic proteins or small molecules such as ATP. We found that this system is particularly responsive to the pro-apoptotic sphingolipid ceramide"
Exocytosis of secretory granule membrane proteins
Exocytosis of specific granule membrane proteins
Deep research review of ORMDL3 function
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Comprehensive literature review covering ORMDL3 as ER-resident SPT regulator, ceramide-dependent feedback mechanism, roles in asthma, immune cell biology, ER stress/UPR, and innate immunity.