Affinage

GRAMD1B

Protein Aster-B · UniProt Q3KR37

Length
738 aa
Mass
85.4 kDa
Annotated
2026-06-10
100 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 3/4 claims corpus-supported (75%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRAMD1B is an endoplasmic reticulum-associated lipid-transfer protein whose GRAM domain functions as a coincidence detector for accessible cholesterol and anionic lipids, including phosphatidylserine, at the plasma membrane (PMID:33604931). Distinct but synergistic binding sites for each lipid couple GRAM-domain cholesterol sensing to membrane tethering and set the rate of non-vesicular cholesterol transport from the plasma membrane to the ER; a human intellectual-disability-associated GRAM-domain mutation selectively abolishes cholesterol sensing while sparing PS sensitivity, and an engineered point mutation conversely enhances cholesterol sensitivity (PMID:33604931). Independently of this lipid-transport role, GRAMD1B operates within JAK/STAT signaling: it is transcriptionally upregulated by JAK/STAT activity and feeds back to maintain STAT3 levels, acting with the pathway to promote cancer cell survival through the anti-apoptotic protein Bcl-xL (PMID:29383166). Loss of GRAMD1B drives membrane ruffling, elevated Rho-family GTPase levels, and enhanced cell migration accompanied by JAK2/STAT3 and Akt activation, positioning GRAMD1B downstream of JAK2 and upstream of Akt as a restraint on the pro-migratory program (PMID:29934528).

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2017 Medium

    Established GRAMD1B as a genetically validated component of JAK/STAT signaling rather than an unconnected ER protein, linking it to a positive feedback loop sustaining STAT3 and to cancer cell survival.

    Evidence RNAi knockdown with STAT3 and Bcl-xL readouts in gastric cancer cells plus genome-wide RNAi epistasis screen of the Drosophila ortholog

    PMID:29383166

    Open questions at the time
    • Molecular mechanism by which GRAMD1B maintains STAT3 levels is undefined
    • Whether the lipid-transfer function relates to the JAK/STAT role is untested
    • Single-lab finding without independent replication
  2. 2018 Medium

    Placed GRAMD1B in a defined signaling hierarchy as a suppressor of cell migration, situating it downstream of JAK2 and upstream of Akt and Rho GTPase regulation.

    Evidence siRNA knockdown, migration assays, Rho GTPase activity assays and pharmacological epistasis (AG490, Akt inhibitor) in MDA-MB-231 breast cancer cells

    PMID:29934528

    Open questions at the time
    • Direct molecular link between GRAMD1B and JAK2/Akt/Rho is not resolved
    • Whether migration phenotype depends on lipid transport activity is unknown
    • Single cell line, single lab
  3. 2021 High

    Defined the biochemical mechanism of GRAMD1B at the membrane, showing its GRAM domain is a dual cholesterol/anionic-lipid coincidence detector that gates non-vesicular cholesterol transport from the PM to the ER.

    Evidence Cell-free reconstitution, lipid-binding assays, site-directed mutagenesis (including a disease mutation), and cell-based transport assays

    PMID:33604931

    Open questions at the time
    • Structural basis of the two distinct lipid-binding sites not resolved
    • Physiological consequences of altered cholesterol transport in tissues not established
    • Relationship to the JAK/STAT signaling role not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How GRAMD1B's biochemically defined cholesterol-transport function mechanistically connects to its role in JAK/STAT signaling and migration control remains unresolved.
  • No experiment tests whether cholesterol transport activity is required for STAT3 maintenance or migration suppression
  • No structural model of the GRAM domain
  • Tissue- and disease-level consequences of the ID-associated mutation uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 1 GO:0140104 molecular carrier activity 1
Localization
GO:0005783 endoplasmic reticulum 1 GO:0005886 plasma membrane 1

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 The GRAM domain of GRAMD1B acts as a coincidence detector for accessible cholesterol and anionic lipids (including phosphatidylserine) at the plasma membrane, with distinct but synergistic binding sites for each. A human intellectual-disability-associated mutation within the GRAM domain specifically impairs cholesterol sensing without affecting PS sensitivity. Another engineered point mutation enhances cholesterol sensitivity without altering PS sensitivity. Cell-free reconstitution and cell-based assays demonstrated that GRAM domain cholesterol sensing regulates membrane tethering and determines the rate of non-vesicular cholesterol transport from the plasma membrane to the ER by GRAMD1b. Cell-free reconstitution, cell-based assays, site-directed mutagenesis, lipid-binding assays The EMBO journal High 33604931
2017 GRAMD1B expression is positively regulated by JAK/STAT signaling in gastric cancer cells, and GRAMD1B knockdown decreases STAT3 levels, indicating a positive feedback loop. GRAMD1B and JAK/STAT signaling act synergistically to promote gastric cancer cell survival by upregulating the anti-apoptotic molecule Bcl-xL. The Drosophila ortholog of GRAMD1B was identified in a genome-wide RNAi screen as a novel component of the JAK/STAT pathway. RNAi knockdown, epistasis analysis (genome-wide RNAi screen in Drosophila), western blotting, immunohistochemistry Oncotarget Medium 29383166
2018 GRAMD1B knockdown in MDA-MB-231 breast cancer cells causes membrane ruffling and protrusions and significantly enhances cell migration, with increased levels of Rho family GTPases. The pro-migratory phenotype induced by GRAMD1B inhibition is associated with JAK2/STAT3 and Akt activation. Epistasis analysis showed that JAK2 inhibition (AG490) increases p-Akt levels via regulation of GRAMD1B expression, placing GRAMD1B downstream of JAK2 and upstream of Akt in this pathway. siRNA knockdown, cell migration assay, western blotting, pharmacological inhibition (JAK2 inhibitor AG490, Akt inhibitor), Rho GTPase activity assay, epistasis analysis Scientific reports Medium 29934528

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Apoptosis (programmed cell death) in arteries of the neonatal lamb. Circulation research 184 7834826
2019 Ruminal microbiome-host crosstalk stimulates the development of the ruminal epithelium in a lamb model. Microbiome 157 31159860
2001 Escherichia coli O157 in cattle and sheep at slaughter, on beef and lamb carcasses and in raw beef and lamb products in South Yorkshire, UK. International journal of food microbiology 130 11252496
2004 Vascular changes after intra-amniotic endotoxin in preterm lamb lungs. American journal of physiology. Lung cellular and molecular physiology 121 15321788
1986 A comparison of energy metabolism in the new-born infant, piglet and lamb. Quarterly journal of experimental physiology (Cambridge, England) 110 3532162
2012 Interaction of bacteriophage l with its E. coli receptor, LamB. Viruses 96 23202520
1986 Mutagenesis by random linker insertion into the lamB gene of Escherichia coli K12. Molecular & general genetics : MGG 94 3027509
1993 Derepression of LamB protein facilitates outer membrane permeation of carbohydrates into Escherichia coli under conditions of nutrient stress. Journal of bacteriology 92 8444809
1989 Functional and nonfunctional LamB signal sequences can be distinguished by their biophysical properties. The Journal of biological chemistry 84 2677003
1981 Post-proline cleaving enzyme from lamb brain. Journal of biochemistry 83 7028730
2007 A small RNA downregulates LamB maltoporin in Salmonella. Molecular microbiology 80 17608792
1984 Intragenic regions required for LamB export. Proceedings of the National Academy of Sciences of the United States of America 76 6374667
2007 Effect of animal (lamb) diet and meat storage on myofibrillar protein oxidation and in vitro digestibility. Meat science 75 22063042
2011 Intra-amniotic LPS and antenatal betamethasone: inflammation and maturation in preterm lamb lungs. American journal of physiology. Lung cellular and molecular physiology 71 22160306
1990 Chemical composition and quality attributes of goat meat and lamb. Meat science 69 22055658
2003 Ewe-lamb bonding behaviours at birth are affected by maternal undernutrition in pregnancy. The British journal of nutrition 68 12568672
2021 Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b. The EMBO journal 65 33604931
1995 Involvement of endothelin-1 in hypoxic pulmonary vasoconstriction in the lamb. The Journal of physiology 56 7714833
1987 Bacteriophage lambda receptor site on the Escherichia coli K-12 LamB protein. Journal of bacteriology 56 2952637
2007 Increased maternal nutrition increases leptin expression in perirenal and subcutaneous adipose tissue in the postnatal lamb. Endocrinology 55 17884936
1999 Perinatal myocardial DNA and protein changes in the lamb: effect of cortisol in the fetus. Pediatric research 54 10447105
1970 Passage of macromolecules between alveolar and interstitial spaces in foetal and newly ventilated lungs of the lamb. The Journal of physiology 53 5500773
2011 Role of Klebsiella pneumoniae LamB Porin in antimicrobial resistance. Antimicrobial agents and chemotherapy 50 21282437
2014 Decreased expression of LamB and Odp1 complex is crucial for antibiotic resistance in Escherichia coli. Journal of proteomics 49 24412198
1979 Interaction of bacteriophage K10 with its receptor, the lamB protein of Escherichia coli. Journal of bacteriology 48 387746
2012 Perinatal lamb model of respiratory syncytial virus (RSV) infection. Viruses 46 23202468
2018 GRAMD1B regulates cell migration in breast cancer cells through JAK/STAT and Akt signaling. Scientific reports 44 29934528
2013 Maternal behaviour and lamb survival: from neuroendocrinology to practical application. Animal : an international journal of animal bioscience 44 24103485
2018 Supranutritional doses of vitamin E to improve lamb meat quality. Meat science 41 30448473
1985 Effects of high-frequency and conventional ventilation on the premature lamb lung. Journal of applied physiology (Bethesda, Md. : 1985) 38 3840801
2019 Fluorescent carbon dots in baked lamb: Formation, cytotoxicity and scavenging capability to free radicals. Food chemistry 37 30827625
1979 Small intestinal morphology and epithelial cell kinetics in lamb rotavirus infections. Gastroenterology 37 218864
2015 IGF-2R-Gαq signaling and cardiac hypertrophy in the low-birth-weight lamb. American journal of physiology. Regulatory, integrative and comparative physiology 36 25632020
2011 Cryptosporidium and Giardia associated with reduced lamb carcase productivity. Veterinary parasitology 35 21719199
2002 Differential effects of leptin on thermoregulation and uncoupling protein abundance in the neonatal lamb. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 12205040
1990 The presence of both the signal sequence and a region of mature LamB protein is required for the interaction of LamB with the export factor SecB. The Journal of biological chemistry 34 2211691
1988 Respective influences of age and weaning on skeletal and visceral muscle protein synthesis in the lamb. The Biochemical journal 34 3223952
2007 Prolificacy and lamb survival at birth in Awassi and Assaf sheep carrying the FecB (Booroola) mutation. Animal reproduction science 33 17997056
1983 Effects of age and weaning on enzyme activities of abomasum and pancreas of the lamb. Journal of dairy science 32 6197430
1983 Mutations in the promoter regions of the malEFG and malK-lamB operons of Escherichia coli K12. Journal of molecular biology 31 6417341
2023 Association of lipidome evolution with the corresponding volatile characteristics of postmortem lamb during chilled storage. Food research international (Ottawa, Ont.) 30 37254350
2021 In Like a Lamb; Out Like a Lion: Marching CAR T Cells Toward Enhanced Efficacy in B-ALL. Molecular cancer therapeutics 30 33903140
2000 A biphasic action of estradiol on estrogen and progesterone receptor expression in the lamb uterus. Reproduction, nutrition, development 30 10943607
1984 Transposon Tn10-dependent expression of the lamB gene in Escherichia coli. Journal of bacteriology 29 6330053
1984 Linker mutagenesis in the gene of an outer membrane protein of Escherichia coli, lamB. Journal of cellular biochemistry 29 6376525
2019 Maltoporin (LamB protein) contributes to the virulence and adhesion of Aeromonas veronii TH0426. Journal of fish diseases 28 30614537
1984 Immunolabelling of bacteriophage lambda receptor protein (LamB) on thin sections of E. coli embedded in Lowicryl. Biology of the cell 28 6084531
1985 Epithelial cell renewal and antibody transfer in the intestine of the foetal and neonatal lamb. The Australian journal of experimental biology and medical science 26 4015549
2020 Influence of dietary inclusion of tannin extracts from mimosa, chestnut and tara on volatile compounds and flavour in lamb meat. Meat science 25 33091724
2003 Maltodextrin transport through lamb. Frontiers in bioscience : a journal and virtual library 25 12700071
2020 Expression of LamB Vaccine Antigen in Wolffia globosa (Duck Weed) Against Fish Vibriosis. Frontiers in immunology 24 32973766
2021 Effects of chilling rate on progression of rigor mortis in postmortem lamb meat. Food chemistry 23 34740047
2020 Synthetic vs. Natural Hydroxytyrosol for Clean Label Lamb Burgers. Antioxidants (Basel, Switzerland) 23 32927869
2002 Mechanism of maltodextrin transport through LamB. Research in microbiology 23 12405347
1987 Effects of glucose infusion on surfactant and glycogen regulation in fetal lamb lung. Journal of applied physiology (Bethesda, Md. : 1985) 23 2826381
1979 Purification and partial characterization of a stimulatory factor for lamb thymus RNA polymerase II. Biochemistry 22 435487
2022 Phosphorylation and acetylation of glycolytic enzymes cooperatively regulate their activity and lamb meat quality. Food chemistry 21 35940100
2022 Transcriptome analysis reveals the molecular regulatory network of muscle development and meat quality in Sunit lamb supplemented with dietary probiotic. Meat science 21 36195032
2007 Polymorphism at the ovine beta3-adrenergic receptor locus (ADRB3) and its association with lamb mortality. Journal of animal science 21 17644783
1983 Phage lambda receptor (lamB protein) in Escherichia coli. Methods in enzymology 21 6228707
2014 Gut inflammation and expression of ICC in a fetal lamb model of fetoscopic intervention for gastroschisis. Surgical endoscopy 20 24648107
1992 Subclinical mastitis in ewes and its effect on lamb performance. Journal of animal science 20 1634391
1987 Protein synthesis and growth in the gastrointestinal tract of the young preruminant lamb. The British journal of nutrition 20 3620435
2023 Integrating identification and targeted proteomics to discover the potential indicators of postmortem lamb meat quality. Meat science 19 36736126
2019 Isolation and Full-Length Sequence Analysis of a Pestivirus from Aborted Lamb Fetuses in Italy. Viruses 19 31412585
1984 Topography of the insertion of LamB protein into the outer membrane of Escherichia coli wild-type and lac-lamB cells. Journal of bacteriology 19 6086567
1981 Arrangement of bacteriophage lambda receptor protein (LamB) in the cell surface of Escherichia coli: a reconstitution study. Journal of bacteriology 19 6455415
2015 Microstructural, protein denaturation and water holding properties of lamb under pulse vacuum brining. Meat science 18 26658008
2009 Whole genome sequencing of lamb rotavirus and comparative analysis with other mammalian rotaviruses. Virus genes 18 19214729
1987 Sequence determinants in the lamB gene of Escherichia coli influencing the binding and pore selectivity of maltoporin. Gene 18 3301537
2009 Metabolic maturity at birth and neonate lamb survival: association among maternal factors, litter size, lamb birth weight, and plasma metabolic and endocrine factors on survival and behavior. Journal of animal science 17 19897628
1989 Antibodies against synthetic peptides and the topology of LamB, an outer membrane protein from Escherichia coli K12. Biochemistry 17 2532541
2017 GRAM domain-containing protein 1B (GRAMD1B), a novel component of the JAK/STAT signaling pathway, functions in gastric carcinogenesis. Oncotarget 16 29383166
2017 Maltoporin LamB Unfolds β Hairpins along Mechanical Stress-Dependent Unfolding Pathways. Structure (London, England : 1993) 15 28625789
2006 Association analyses between the prion protein locus and reproductive and lamb weight traits in Ripollesa sheep. Journal of animal science 15 17060422
2005 ATP depletion and cell death in the neonatal lamb ductus arteriosus. Pediatric research 15 15774827
2000 Platelet-activating factor receptors in lamb lungs are downregulated immediately after birth. American journal of physiology. Heart and circulatory physiology 15 10749711
1977 Lamb and mutton flavour: Contributing factors and chemical aspects. Meat science 15 22054553
1996 Survival and growth of Aeromonas hydrophila on modified atmosphere packaged normal and high pH lamb. International journal of food microbiology 14 8652346
1994 Fine structure of taste buds located on the lamb epiglottis. The Anatomical record 14 8192249
2019 Prepartum fatty acid supplementation in sheep. IV. Effect of calcium salts with eicosapentaenoic acid and docosahexaenoic acid in the maternal and finishing diet on lamb liver and adipose tissue during the lamb finishing period1. Journal of animal science 13 31063536
2019 Lamb as a potential source of Toxoplasma gondii infection for Australians. Australian and New Zealand journal of public health 13 31825558
2013 Developmental changes in diaphragm muscle function in the preterm and postnatal lamb. Pediatric pulmonology 13 23401383
1986 Expression of the Escherichia coli lamB gene in Vibrio cholerae. Microbial pathogenesis 13 2977630
1981 rho Mutations restore lamB expression in E. coli K12 strains with an inactive malB region. Molecular & general genetics : MGG 13 6278260
2022 Respiratory strategy at birth initiates distinct lung injury phenotypes in the preterm lamb lung. Respiratory research 12 36517795
2020 Lamb Fattening Under Intensive Pasture-Based Systems: A Review. Animals : an open access journal from MDPI 12 32120943
1985 [Protein metabolism in the newborn lamb. II. Influence of diet on protein synthesis and turnover]. Reproduction, nutrition, developpement 12 4095376
2020 The effects of improving low dietary protein utilization on the proteome of lamb tissues. Journal of proteomics 11 32380293
2018 Comparison of transcriptomic landscapes of different lamb muscles using RNA-Seq. PloS one 11 30040835
2013 Expression of calpastatin and myostatin genes associated with lamb meat quality. Genetics and molecular research : GMR 11 24338411
1983 Maturation of the hypothalamic--pituitary--gonadal axis in the male lamb: a review. Psychoneuroendocrinology 11 6413998
2022 miRNA transcriptome and myofiber characteristics of lamb skeletal muscle during hypertrophic growth1. Frontiers in genetics 10 36419828
1995 Impact of composition manipulation on lean lamb production in the United States. Journal of animal science 10 8567487
1991 Fish meal as a protein supplement in finishing lamb diets. Journal of animal science 10 2066322
2022 Evaluation of the Links between Lamb Feed Efficiency and Rumen and Plasma Metabolomic Data. Metabolites 9 35448491
2021 Detection of Infectious Cryptosporidium parvum Oocysts from Lamb's Lettuce: CC-qPCR's Intake. Microorganisms 9 33494236
2020 Distinct patterns of mutational sensitivity for λ resistance and maltodextrin transport in Escherichia coli LamB. Microbial genomics 9 32238226
2019 Transcriptomic Revelation of Phenolic Compounds Involved in Aluminum Toxicity Responses in Roots of Cunninghamia lanceolata (Lamb.) Hook. Genes 9 31652726
2023 Clinical characterization of Lamb-Shaffer syndrome: a case report and literature review. BMC medical genomics 8 36759900

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