Affinage

EBP

3-beta-hydroxysteroid-Delta(8),Delta(7)-isomerase · UniProt Q15125

Round 2 corrected
Length
230 aa
Mass
26.4 kDa
Annotated
2026-04-28
130 papers in source corpus 2 papers cited in narrative 2 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

EBP encodes the Δ8,Δ7 sterol isomerase (emopamil-binding protein), an enzyme required for cholesterol biosynthesis that catalyzes the conversion of Δ8-sterols to Δ7-sterols. Loss-of-function mutations in EBP cause X-linked dominant chondrodysplasia punctata type 2 (CDPX2), and patients carrying nonsense EBP mutations accumulate Δ8-sterols, confirming the enzymatic role of EBP in the sterol biosynthetic pathway (PMID:11038443). Somatic mosaicism for EBP mutations recapitulates the mosaic phenotype of CDPX2, indicating that EBP function is required cell-autonomously for normal skeletal and skin development (PMID:12503102).

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2000 Medium

    Establishing EBP as the causative gene for CDPX2 resolved the molecular basis of this X-linked skeletal dysplasia and confirmed that the encoded protein functions as a Δ8,Δ7 sterol isomerase in vivo, as patient nonsense mutations produced sterol profiles diagnostic of blocked isomerase activity.

    Evidence EBP sequencing in multiple CDPX2 patients combined with biochemical sterol profiling

    PMID:11038443

    Open questions at the time
    • No direct in vitro enzymatic reconstitution of human EBP isomerase activity was performed
    • Structural basis for substrate recognition and catalysis remains undefined
    • Genotype–phenotype correlation across the full mutation spectrum not established
  2. 2003 Low

    Demonstrating that somatic mosaicism for an EBP mutation in a male recapitulates the mosaic CDPX2 phenotype established that EBP is required cell-autonomously, distinguishing mosaic loss of function from the random X-inactivation mechanism operative in heterozygous females.

    Evidence Molecular genetic and sterol profiling analysis of a single mosaic male CDPX2 patient

    PMID:12503102

    Open questions at the time
    • Single case report; not independently confirmed in additional mosaic individuals
    • Tissue-specific requirements for EBP in skeletal versus skin lineages not dissected
    • No functional rescue experiment performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • The catalytic mechanism, three-dimensional structure, and complete genotype–phenotype landscape of EBP remain uncharacterized in the primary literature captured here; whether EBP has additional non-enzymatic roles (e.g., its original identification as an emopamil/sigma-ligand-binding protein) is unresolved.
  • No crystal or cryo-EM structure available
  • No in vitro reconstitution of isomerase activity with purified human EBP
  • Pharmacological significance of emopamil binding versus isomerase activity not delineated

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016853 isomerase activity 1
Pathway
R-HSA-1430728 Metabolism 1

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Loss-of-function mutations in the EBP gene (encoding Δ8,Δ7 sterol isomerase / emopamil-binding protein) cause X-linked dominant chondrodysplasia punctata type 2 (CDPX2); patients with nonsense EBP mutations displayed abnormal sterol profiles consistent with a defect in Δ8,Δ7 sterol isomerase activity, establishing EBP as the causative gene and confirming its enzymatic role in sterol biosynthesis. DNA sequencing of EBP in CDPX2 patients combined with sterol profile analysis (biochemical phenotyping) in patients with nonsense mutations American journal of medical genetics Medium 11038443
2003 CDPX2 (X-linked dominant chondrodysplasia punctata) can arise from somatic mosaicism for an EBP (sterol-Δ8-Δ7 isomerase) gene mutation, demonstrating that the EBP protein product is required cell-autonomously for normal skeletal and skin development and that mosaicism for loss of EBP function recapitulates the mosaic phenotype normally attributed to random X-inactivation in heterozygous females. Molecular genetic analysis (EBP sequencing) and biochemical sterol profiling in a mosaic male patient with CDPX2 clinical features American journal of medical genetics. Part A Low 12503102

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1991 Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes & development 1511 1840554
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2006 Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging cell 1124 16626397
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1988 Isolation of a recombinant copy of the gene encoding C/EBP. Genes & development 926 2850264
2002 Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 879 11927518
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. Genes & development 688 18981473
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1989 The DNA binding domain of the rat liver nuclear protein C/EBP is bipartite. Science (New York, N.Y.) 611 2494700
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
1996 Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Molecular and cellular biology 592 8754828
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
1995 Conditional ectopic expression of C/EBP beta in NIH-3T3 cells induces PPAR gamma and stimulates adipogenesis. Genes & development 456 7557387
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
1968 Generalized gangliosidosis: beta-galactosidase deficiency. Science (New York, N.Y.) 421 5647842
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1996 The human cytosolic molecular chaperones hsp90, hsp70 (hsc70) and hdj-1 have distinct roles in recognition of a non-native protein and protein refolding. The EMBO journal 357 8670798
2002 Surface sensing and adhesion of Escherichia coli controlled by the Cpx-signaling pathway. Proceedings of the National Academy of Sciences of the United States of America 305 11830644
1992 Differential expression of three C/EBP isoforms in multiple tissues during the acute phase response. The Journal of biological chemistry 280 1371993
2012 Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. Nature genetics 278 23042114
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
1998 The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Molecular and cellular biology 238 9418879
2005 Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. Journal of cell science 237 15944395
1997 The sigma(E) and the Cpx signal transduction systems control the synthesis of periplasmic protein-folding enzymes in Escherichia coli. Genes & development 225 9159399
1995 The C/EBP family of transcription factors. Immunobiology 220 8530141
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
1996 C/EBP, c-Myb, and PU.1 cooperate to regulate the neutrophil elastase promoter. Molecular and cellular biology 208 8756629
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1989 Cognate DNA binding specificity retained after leucine zipper exchange between GCN4 and C/EBP. Science (New York, N.Y.) 200 2530632
1999 The Cpx envelope stress response is controlled by amplification and feedback inhibition. Journal of bacteriology 195 10464196
2008 GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Molecular genetics and metabolism 194 18524657
2013 C/EBP maintains chromatin accessibility in liver and facilitates glucocorticoid receptor recruitment to steroid response elements. The EMBO journal 188 23665916
2012 C/EBP transcription factors mediate epicardial activation during heart development and injury. Science (New York, N.Y.) 188 23160954
2008 Characterization of the Cpx regulon in Escherichia coli strain MC4100. Journal of bacteriology 181 19103922
1997 CREB controls LAP/C/EBP beta transcription. Molecular and cellular biology 175 9199295
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2013 Everything old is new again: an update on current research on the Cpx envelope stress response. Biochimica et biophysica acta 170 24184210
2021 Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans. Aging cell 164 33939265
2017 Transcription Factor C/EBP Homologous Protein in Health and Diseases. Frontiers in immunology 164 29230213
1994 C/EBP beta regulation of the tumor necrosis factor alpha gene. The Journal of clinical investigation 161 7929820
2003 Dominant-negative C/EBP disrupts mitotic clonal expansion and differentiation of 3T3-L1 preadipocytes. Proceedings of the National Academy of Sciences of the United States of America 157 14688407
1993 The 67-kD elastin/laminin-binding protein is related to an enzymatically inactive, alternatively spliced form of beta-galactosidase. The Journal of clinical investigation 157 8383699
2011 Just scratching the surface: an expanding view of the Cpx envelope stress response. FEMS microbiology letters 154 22092948
1998 The 67-kDa enzymatically inactive alternatively spliced variant of beta-galactosidase is identical to the elastin/laminin-binding protein. The Journal of biological chemistry 154 9497360
1999 The sigmaE and Cpx regulatory pathways: overlapping but distinct envelope stress responses. Current opinion in microbiology 147 10322173
2001 Altered expression of C/EBP family members results in decreased adipogenesis with aging. American journal of physiology. Regulatory, integrative and comparative physiology 145 11353682
1988 Saccharomyces cerevisiae cho2 mutants are deficient in phospholipid methylation and cross-pathway regulation of inositol synthesis. Genetics 145 3066687
2013 In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. Proteomics 138 23533145
1985 Human placental neuraminidase. Activation, stabilization and association with beta-galactosidase and its protective protein. European journal of biochemistry 134 3922758
2002 Mechanism of c-Myb-C/EBP beta cooperation from separated sites on a promoter. Cell 133 11792321
2004 A novel CPx-ATPase from the cadmium hyperaccumulator Thlaspi caerulescens. FEBS letters 131 15225623
2005 Lysosomal sialidase (neuraminidase-1) is targeted to the cell surface in a multiprotein complex that facilitates elastic fiber assembly. The Journal of biological chemistry 130 16314420
2005 Transcription profiling of C/EBP targets identifies Per2 as a gene implicated in myeloid leukemia. Blood 127 15985538
2013 Proteomic analysis of podocyte exosome-enriched fraction from normal human urine. Journal of proteomics 126 23376485
1997 Cloning of the novel human myeloid-cell-specific C/EBP-epsilon transcription factor. Molecular and cellular biology 124 9032264
2006 The Cpx system of Escherichia coli, a strategic signaling pathway for confronting adverse conditions and for settling biofilm communities? Research in microbiology 123 16487683
1991 DNA-induced increase in the alpha-helical content of C/EBP and GCN4. Biochemistry 114 1892816
2001 The role of C/EBP(epsilon) in the terminal stages of granulocyte differentiation. Stem cells (Dayton, Ohio) 110 11239167
1995 Ig/EBP (C/EBP gamma) is a transdominant negative inhibitor of C/EBP family transcriptional activators. Nucleic acids research 108 7501458
2011 Signal integration by the Cpx-envelope stress system. FEMS microbiology letters 104 22092888
1998 The C/EBP family of transcription factors in the liver and other organs. International journal of experimental pathology 104 10319019
2000 C/EBP regulates hepatic transcription of 11beta -hydroxysteroid dehydrogenase type 1. A novel mechanism for cross-talk between the C/EBP and glucocorticoid signaling pathways. The Journal of biological chemistry 102 10906322
1996 C/EBP activators are required for HIV-1 replication and proviral induction in monocytic cell lines. Immunity 91 8758898
2011 IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM. Blood 83 21389327
2002 Calreticulin interacts with C/EBPalpha and C/EBPbeta mRNAs and represses translation of C/EBP proteins. Molecular and cellular biology 81 12242300
2019 CPX Targeting DJ-1 Triggers ROS-induced Cell Death and Protective Autophagy in Colorectal Cancer. Theranostics 78 31534504
2014 The Cpx envelope stress response modifies peptidoglycan cross-linking via the L,D-transpeptidase LdtD and the novel protein YgaU. Journal of bacteriology 74 25422305
2002 C/EBP DNA-binding activity is upregulated by a glucocorticoid-dependent mechanism in septic muscle. American journal of physiology. Regulatory, integrative and comparative physiology 74 11792653
1992 Drosophila C/EBP: a tissue-specific DNA-binding protein required for embryonic development. Genes & development 68 1459454
2018 Localized hypoxia links ER stress to lung fibrosis through induction of C/EBP homologous protein. JCI insight 67 30135303
2011 C/EBP-δ regulates VEGF-C autocrine signaling in lymphangiogenesis and metastasis of lung cancer through HIF-1α. Oncogene 67 21666710
2007 The interferon signaling network and transcription factor C/EBP-beta. Cellular & molecular immunology 66 18163952
2013 C/EBP homologous protein drives pro-catabolic responses in chondrocytes. Arthritis research & therapy 62 24351550
2003 The Papillomavirus E2 protein binds to and synergizes with C/EBP factors involved in keratinocyte differentiation. Journal of virology 60 12692227
2002 Regulation of CCAAT/enhancer-binding protein (C/EBP) activator proteins by heterodimerization with C/EBPgamma (Ig/EBP). The Journal of biological chemistry 60 11980905
2000 Sp1 and C/EBP are necessary to activate the lactoferrin gene promoter during myeloid differentiation. Blood 60 10845904
2008 Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 58 18832658
2000 Novel and recurrent EBP mutations in X-linked dominant chondrodysplasia punctata. American journal of medical genetics 54 11038443
2019 The Lipoprotein NlpE Is a Cpx Sensor That Serves as a Sentinel for Protein Sorting and Folding Defects in the Escherichia coli Envelope. Journal of bacteriology 51 30833359
2002 C/EBP-beta, C/EBP-delta, PU.1, AML1 genes: mutational analysis in 381 samples of hematopoietic and solid malignancies. Leukemia research 50 11916518
2001 Molecular cloning, genetic mapping, and expression analysis of four zebrafish c/ebp genes. Gene 50 11750126
2015 Endogenous prostaglandin E2 potentiates anti-inflammatory phenotype of macrophage through the CREB-C/EBP-β cascade. European journal of immunology 48 26118414
2003 Transcription cooperation by NFAT.C/EBP composite enhancer complex. The Journal of biological chemistry 48 12606546
1996 Control of adipocyte differentiation by CCAAT/enhancer binding protein alpha (C/EBP alpha). International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity 48 8680485
2017 Zinc transporter ZIP13 suppresses beige adipocyte biogenesis and energy expenditure by regulating C/EBP-β expression. PLoS genetics 46 28854265
2005 Cooperative interaction of C/EBP beta and Tat modulates MCP-1 gene transcription in astrocytes. Journal of neuroimmunology 46 15710476
2011 Stress-induced C/EBP homology protein (CHOP) represses MyoD transcription to delay myoblast differentiation. PloS one 44 22242125
2001 C/EBP epsilon mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut). Proceedings of the National Academy of Sciences of the United States of America 44 11438745
2015 The role of C/EBP-β LIP in multidrug resistance. Journal of the National Cancer Institute 42 25766403
2012 Inhibition of CD200R1 expression by C/EBP β in reactive microglial cells. Journal of neuroinflammation 42 22776069
1999 Identification of mouse CPX-1, a novel member of the metallocarboxypeptidase gene family with highest similarity to CPX-2. DNA and cell biology 42 10073577
2020 C/EBPɑ is crucial determinant of epithelial maintenance by preventing epithelial-to-mesenchymal transition. Nature communications 41 32034145
1993 Differential adrenergic regulation of C/EBP alpha and C/EBP beta in brown adipose tissue. FEBS letters 41 8440378
2014 The Vibrio cholerae Cpx envelope stress response senses and mediates adaptation to low iron. Journal of bacteriology 40 25368298
2014 miRNA-130a regulates C/EBP-ε expression during granulopoiesis. Blood 39 24398327
2003 X-linked dominant chondrodysplasia punctata (CDPX2) caused by single gene mosaicism in a male. American journal of medical genetics. Part A 39 12503102
2007 Influence of the Cpx extracytoplasmic-stress-responsive pathway on Yersinia sp.-eukaryotic cell contact. Infection and immunity 38 17620356
2016 C/EBP homologous protein modulates liraglutide-mediated attenuation of non-alcoholic steatohepatitis. Laboratory investigation; a journal of technical methods and pathology 37 27239734
2014 The Cpx envelope stress response regulates and is regulated by small noncoding RNAs. Journal of bacteriology 37 25246476
2003 Regulation of Bcl-2 expression by C/EBP in t(14;18) lymphoma cells. Oncogene 37 12970736
2013 Reciprocal modulation of C/EBP-α and C/EBP-β by IL-13 in activated microglia prevents neuronal death. European journal of immunology 36 23881867
2020 Roles of C/EBP class bZip proteins in the growth and cell competition of Rp ('Minute') mutants in Drosophila. eLife 35 31909714
2013 Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration. PloS one 35 23646198
2004 Identification of murine and human XCP1 genes as C/EBP-epsilon-dependent members of FIZZ/Resistin gene family. Oncogene 35 15064728
2009 Genetic analysis of activation of the Vibrio cholerae Cpx pathway. Journal of bacteriology 34 19542291
2004 Suppression of C/EBP alpha expression in biliary cell differentiation from hepatoblasts during mouse liver development. Journal of hepatology 34 15519652
2007 C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis. Biochemical and biophysical research communications 33 18166146
2006 C/EBP homologous protein is necessary for normal osteoblastic function. Journal of cellular biochemistry 33 16220546
2018 Loss of C/EBP-β LIP drives cisplatin resistance in malignant pleural mesothelioma. Lung cancer (Amsterdam, Netherlands) 32 29748013
1993 The human C/EBP delta (CRP3/CELF) gene: structure and chromosomal localization. Genomics 32 8314590
2018 Ablation of C/EBP homologous protein attenuates renal fibrosis after ureteral obstruction by reducing autophagy and microtubule disruption. Biochimica et biophysica acta. Molecular basis of disease 31 29425932
2014 Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein. PloS one 31 25314137
2010 Involvement and necessity of the Cpx regulon in the event of aberrant beta-barrel outer membrane protein assembly. Molecular microbiology 31 20487295
2010 C/EBP{delta} and STAT-1 are required for TLR8 transcriptional activity. The Journal of biological chemistry 31 20829351
2016 Coordinated inhibition of C/EBP by Tribbles in multiple tissues is essential for Caenorhabditis elegans development. BMC biology 30 27927209
2012 Artemisinic acid is a regulator of adipocyte differentiation and C/EBP δ expression. Journal of cellular biochemistry 28 22396222
1996 Functional characterization of the repeated UASINO element in the promoters of the INO1 and CHO2 genes of yeast. Yeast (Chichester, England) 28 8810039
2023 Envelope-Stress Sensing Mechanism of Rcs and Cpx Signaling Pathways in Gram-Negative Bacteria. Journal of microbiology (Seoul, Korea) 27 36892778
2011 Role of C/EBP-β, p38 MAPK, and MKK6 in IL-1β-mediated C3 gene regulation in astrocytes. Journal of cellular biochemistry 27 21308746
2018 Impaired DNA demethylation of C/EBP sites causes premature aging. Genes & development 26 29884649
2011 C/EBP-α and C/EBP-β-mediated adipogenesis of human mesenchymal stem cells (hMSCs) using PLGA nanoparticles complexed with poly(ethyleneimmine). Biomaterials 26 21600648
2009 Cyclic regulation of transcription factor C/EBP beta in human endometrium. Reproductive biology and endocrinology : RB&E 25 19222842
2024 CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance, and immune homeostasis. Blood 24 38227935
2016 Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24 27006448