Affinage

NRDC

Nardilysin · UniProt O43847

Length
1151 aa
Mass
131.7 kDa
Annotated
2026-06-10
49 papers in source corpus 6 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NRDC (nardilysin) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates N-terminal to paired basic residues (Arg or Lys) and serves as a regulator of growth-factor signaling and tissue invasion (PMID:12095415). Its catalytic activity is controlled by an internal ~90-residue acidic domain (DAC) positioned near the active site: HB-EGF, acting through its heparin-binding P21 region, binds the DAC to potently inhibit peptidase activity in a Ca2+-dependent manner, with disulfide-bonded P21 dimers required for inhibition (PMID:12095415). NRDC's role in HB-EGF biology is partly enzyme-independent, since an active-site mutant still enhances HB-EGF-induced cell migration (PMID:12095415). In cancer cells, NRDC drives invasion by maintaining MMP2 and MMP3 expression (PMID:24168165) and supports proliferation and survival through cyclin D1, including EGF-induced cyclin D1 upregulation, without altering bulk AKT or MAPK signaling (PMID:21769958). Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder, and developmental lethality of Drosophila Nrdc-null mutants is fully rescued by wild-type human NRDC, establishing functional conservation (PMID:41734767).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2002 High

    Established that NRDC is a basic-pair-cleaving metalloendopeptidase whose activity is gated by an internal acidic domain and HB-EGF, and crucially that its migration-promoting function is separable from its catalytic activity.

    Evidence In vitro enzymatic assays, active-site mutagenesis, and domain-binding studies with recombinant HB-EGF P21 and the NRDC DAC domain

    PMID:12095415

    Open questions at the time
    • Physiological substrates cleaved in cells not defined
    • Structural basis of DAC/P21/active-site interaction not resolved
    • Mechanism by which the active-site mutant still enhances migration unexplained
  2. 2002 Medium

    Refined the NRDC protein definition by showing translation initiates at Met49 rather than the first predicted methionine, clarifying the functional protein boundary.

    Evidence Biochemical characterization of recombinant NRDC protein

    PMID:12095415

    Open questions at the time
    • Single-lab determination
    • Functional consequence of the upstream sequence not addressed
  3. 2011 Medium

    Connected NRDC to cancer cell proliferation and survival, placing it upstream of cyclin D1 in EGF-driven growth control.

    Evidence siRNA knockdown in MCF10CA1h and MDA-MB-231 breast cancer cells with proliferation, apoptosis, and cyclin D1 western readouts

    PMID:21769958

    Open questions at the time
    • No rescue to confirm specificity
    • Mechanism linking NRDC to cyclin D1 not defined given unchanged AKT/MAPK
    • Single lineage tested
  4. 2013 Medium

    Defined a pro-invasive role for NRDC, placing it upstream of MMP2 and MMP3 expression in squamous carcinoma.

    Evidence siRNA knockdown in esophageal squamous cell carcinoma lines (TE1, TE5) with invasion assays and MMP2/MMP3 RT-PCR

    PMID:24168165

    Open questions at the time
    • Mechanism of MMP transcriptional control unknown
    • Dependence on catalytic activity not tested
    • No in vivo validation
  5. 2025 Medium

    Implicated NRDC in muscle metabolic regulation as a miR-136-3p target, linking it to mitochondrial/glycolytic balance and myogenic gene expression.

    Evidence miR-136-3p and siRNA NRDC knockdown in human myotubes with glucose uptake, mitochondrial profiling, and gene expression assays

    PMID:41046976

    Open questions at the time
    • Molecular substrate underlying the metabolic shift unidentified
    • Whether effect requires peptidase activity untested
    • Single cell system
  6. 2026 High

    Established NRDC as a disease gene, demonstrating that biallelic loss-of-function causes a severe neurodevelopmental disorder with cross-species functional conservation.

    Evidence Exome sequencing of 14 individuals across 9 families, Drosophila null rescue with human NRDC, and minigene/RT-PCR splicing assays

    PMID:41734767

    Open questions at the time
    • Neurodevelopmental substrate/pathway of NRDC not defined
    • Relationship between disease mechanism and the HB-EGF/peptidase axis unresolved
  7. 2026 Low

    Positioned NRDC as a downstream effector promoting AML cell differentiation within a CDC5L/ADAP1 transcriptional axis.

    Evidence lncRNA AC098613.1 overexpression, CDC5L stability and transcription analyses, and xenograft growth in THP-1/HL-60 cells

    PMID:41663817

    Open questions at the time
    • NRDC placement is indirect, downstream of CDC5L/ADAP1, with little direct NRDC mechanistic data
    • No demonstration that NRDC enzymatic activity drives differentiation
    • Single study

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological substrates of NRDC and the molecular pathway linking its peptidase/HB-EGF function to its neurodevelopmental and metabolic roles remain undefined.
  • No in vivo substrate identified
  • Mechanistic bridge between catalytic activity and developmental phenotypes missing
  • Relative contribution of enzyme-dependent vs enzyme-independent functions in disease unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 1 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1266738 Developmental Biology 1 R-HSA-162582 Signal Transduction 1
Partners
HBEGF

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Nardilysin (NRDc/NRDC) is a cytosolic and cell-surface metalloendopeptidase that cleaves substrates upstream of Arg or Lys in basic pairs in vitro. The protein contains a ~90 amino acid acidic domain (DAC) inserted near its active site. HB-EGF potently inhibits NRDc enzymatic activity through an interaction involving the 21 amino acid heparin-binding domain (P21) of HB-EGF, the DAC of NRDc, and likely its active site. Disulfide-bonded P21 dimers are required for inhibition. Ca2+ regulates both NRDc activity and HB-EGF binding via the DAC. An active-site mutant of NRDc retains the ability to enhance HB-EGF-induced cell migration, demonstrating that enzyme activity is dispensable for this function. In vitro enzymatic assays, active-site mutagenesis, binding studies with recombinant protein domains The Biochemical journal High 12095415
2002 NRDc/NRDC protein translation initiates at Met49, not at the first predicted methionine. Biochemical characterization of recombinant NRDc protein The Biochemical journal Medium 12095415
2013 Knockdown of NRD1 (nardilysin/NRDC) in esophageal squamous cell carcinoma cell lines (TE1 and TE5) reduced cell invasiveness and significantly decreased MMP2 and MMP3 mRNA expression, placing NRDC upstream of MMP2/MMP3 in a pro-invasive pathway. siRNA knockdown, invasion assay, RT-PCR for MMP2/MMP3 expression Cancer science Medium 24168165
2011 Silencing of NRD1 (nardilysin/NRDC) in MCF10CA1h and MDA-MB-231 breast cancer cells reduced proliferation and growth, increased apoptotic cell population, and reduced cyclin D1 expression (including EGF-induced cyclin D1 upregulation), without affecting overall AKT or MAPK activation downstream of EGF signaling. siRNA knockdown, cell proliferation assay, flow cytometry (apoptosis), western blot for cyclin D1, AKT, MAPK Genes, chromosomes & cancer Medium 21769958
2025 miR-136-3p targets the NRDC gene (nardilysin convertase) in human myotubes. Silencing of NRDC mimicked the effect of miR-136-3p transfection, inducing a shift toward glycolytic metabolism in mitochondria and modulating myogenesis-related gene expression, and enhancing glucose uptake. miRNA transfection, siRNA knockdown of NRDC, glucose uptake assay, mitochondrial metabolic profiling, gene expression analysis in human myotubes Journal of sport and health science Medium 41046976
2026 Biallelic loss-of-function variants in NRDC cause a severe neurodevelopmental disorder. Drosophila dNrdc null mutants show developmental lethality that is fully rescued by wild-type human NRDC, confirming functional conservation. Missense variants cause partial lethality consistent with hypomorphic function. Splice variants lead to exon skipping confirmed by RT-PCR and minigene assay in HEK293T cells. Human genetics (exome sequencing of 14 individuals), Drosophila null mutant rescue with human NRDC, minigene splicing assay in HEK293T cells, RT-PCR from patient fibroblasts American journal of human genetics High 41734767
2026 NRDC (nardilysin) promotes AML cell differentiation downstream of CDC5L and ADAP1; overexpression of lncRNA AC098613.1 stabilizes CDC5L, which transcriptionally activates ADAP1 and NRD1/NRDC expression, inducing differentiation of THP-1 and HL-60 cells. lncRNA overexpression, CDC5L stability assay, ChIP/transcription analysis, in vivo xenograft tumor growth Apoptosis Low 41663817

Source papers

Stage 0 corpus · 49 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 RNA-binding protein Nrd1 directs poly(A)-independent 3'-end formation of RNA polymerase II transcripts. Nature 318 11565036
2006 Nrd1 interacts with the nuclear exosome for 3' processing of RNA polymerase II transcripts. Molecular cell 254 16427013
2008 The Nrd1-Nab3-Sen1 termination complex interacts with the Ser5-phosphorylated RNA polymerase II C-terminal domain. Nature structural & molecular biology 238 18660819
2006 Termination of cryptic unstable transcripts is directed by yeast RNA-binding proteins Nrd1 and Nab3. Molecular cell 223 16973436
2006 Transcription termination and nuclear degradation of cryptic unstable transcripts: a role for the nrd1-nab3 pathway in genome surveillance. Molecular cell 202 16973437
2014 PAR-CLIP data indicate that Nrd1-Nab3-dependent transcription termination regulates expression of hundreds of protein coding genes in yeast. Genome biology 142 24393166
2011 Transcriptome-wide binding sites for components of the Saccharomyces cerevisiae non-poly(A) termination pathway: Nrd1, Nab3, and Sen1. PLoS genetics 123 22028667
2006 Regulation of yeast NRD1 expression by premature transcription termination. Molecular cell 119 16507362
2007 Interaction of yeast RNA-binding proteins Nrd1 and Nab3 with RNA polymerase II terminator elements. RNA (New York, N.Y.) 113 17237360
2012 Serine phosphorylation and proline isomerization in RNAP II CTD control recruitment of Nrd1. Genes & development 93 22892239
1998 Control of pre-mRNA accumulation by the essential yeast protein Nrd1 requires high-affinity transcript binding and a domain implicated in RNA polymerase II association. Proceedings of the National Academy of Sciences of the United States of America 85 9618475
2011 Yeast Nrd1, Nab3, and Sen1 transcriptome-wide binding maps suggest multiple roles in post-transcriptional RNA processing. RNA (New York, N.Y.) 81 21954178
2012 In vivo SELEX reveals novel sequence and structural determinants of Nrd1-Nab3-Sen1-dependent transcription termination. The EMBO journal 63 23032188
2009 The Ess1 prolyl isomerase is required for transcription termination of small noncoding RNAs via the Nrd1 pathway. Molecular cell 63 19854134
2011 H3K4 trimethylation by Set1 promotes efficient termination by the Nrd1-Nab3-Sen1 pathway. Molecular and cellular biology 56 21709022
2015 The exosome component Rrp6 is required for RNA polymerase II termination at specific targets of the Nrd1-Nab3 pathway. PLoS genetics 49 25680078
2016 The Nrd1-like protein Seb1 coordinates cotranscriptional 3' end processing and polyadenylation site selection. Genes & development 46 27401558
2012 Interactions of Sen1, Nrd1, and Nab3 with multiple phosphorylated forms of the Rpb1 C-terminal domain in Saccharomyces cerevisiae. Eukaryotic cell 43 22286094
2019 RNA Polymerase II CTD Tyrosine 1 Is Required for Efficient Termination by the Nrd1-Nab3-Sen1 Pathway. Molecular cell 39 30639244
2012 Budding yeast telomerase RNA transcription termination is dictated by the Nrd1/Nab3 non-coding RNA termination pathway. Nucleic acids research 39 22379137
2009 Role of the RNA-binding protein Nrd1 and Pmk1 mitogen-activated protein kinase in the regulation of myosin mRNA stability in fission yeast. Molecular biology of the cell 32 19279143
2012 The Saccharomyces cerevisiae Nrd1-Nab3 transcription termination pathway acts in opposition to Ras signaling and mediates response to nutrient depletion. Molecular and cellular biology 31 22431520
2015 Nab3 facilitates the function of the TRAMP complex in RNA processing via recruitment of Rrp6 independent of Nrd1. PLoS genetics 30 25775092
2010 Nuclear mRNA quality control in yeast is mediated by Nrd1 co-transcriptional recruitment, as revealed by the targeting of Rho-induced aberrant transcripts. Nucleic acids research 28 21113025
2004 Interaction between a negative regulator (Msa2/Nrd1) and a positive regulator (Cpc2) of sexual differentiation in Schizosaccharomyces pombe. Bioscience, biotechnology, and biochemistry 25 15277777
2013 NRD1, which encodes nardilysin protein, promotes esophageal cancer cell invasion through induction of MMP2 and MMP3 expression. Cancer science 24 24168165
2013 The RNA polymerase II C-terminal domain-interacting domain of yeast Nrd1 contributes to the choice of termination pathway and couples to RNA processing by the nuclear exosome. The Journal of biological chemistry 24 24196955
2012 Role of the RNA-binding protein Nrd1 in stress granule formation and its implication in the stress response in fission yeast. PloS one 24 22276125
2002 The metalloendopeptidase nardilysin (NRDc) is potently inhibited by heparin-binding epidermal growth factor-like growth factor (HB-EGF). The Biochemical journal 20 12095415
2013 A network of interdependent molecular interactions describes a higher order Nrd1-Nab3 complex involved in yeast transcription termination. The Journal of biological chemistry 18 24100036
2022 Loss of function of the bHLH transcription factor Nrd1 in tomato enhances resistance to Pseudomonas syringae. Plant physiology 11 35751605
2019 Identification of Three Sequence Motifs in the Transcription Termination Factor Sen1 that Mediate Direct Interactions with Nrd1. Structure (London, England : 1993) 11 31104813
2017 The structure of transcription termination factor Nrd1 reveals an original mode for GUAA recognition. Nucleic acids research 10 28973465
2014 Structure and semi-sequence-specific RNA binding of Nrd1. Nucleic acids research 10 24860164
2011 Elevated NRD1 metalloprotease expression plays a role in breast cancer growth and proliferation. Genes, chromosomes & cancer 9 21769958
2025 Exercise training-induced extracellular miR-136-3p modulates glucose uptake and myogenesis through targeting of NRDC in human skeletal muscle. Journal of sport and health science 6 41046976
2023 The Nrd1-Nab3-Sen1 transcription termination complex from a structural perspective. Biochemical Society transactions 6 37222282
2024 Tho2-mediated escort of Nrd1 regulates the expression of aging-related genes. Aging cell 5 38769776
2011 1H, 13C, and 15N resonance assignments for the CTD-interacting domain of Nrd1 bound to Ser5-phosphorylated CTD of RNA polymerase II. Biomolecular NMR assignments 5 21350922
2022 Structural basis of Nrd1-Nab3 heterodimerization. Life science alliance 4 35022249
2013 Structure of the second RRM domain of Nrd1, a fission yeast MAPK target RNA binding protein, and implication for its RNA recognition and regulation. Biochemical and biophysical research communications 4 23770370
2017 Chemical shift assignments of the first and second RRMs of Nrd1, a fission yeast MAPK-target RNA binding protein. Biomolecular NMR assignments 3 28284018
2022 Altered Levels of Negative Costimulatory Molecule V-Set Domain-Containing T-Cell Activation Inhibitor-1 (VTCN1) and Metalloprotease Nardilysin (NRD1) are Associated with Generalized Active Vitiligo. Immunological investigations 2 35815687
2025 The functionality of telomerase depends on CPF-CF induced 3'end processing of its RNA component TLC1 and a novel Nrd1-Nab3 surveillance mechanism. Nucleic acids research 1 40488281
2026 LncRNA AC098613.1 promotes acute myeloid leukemia cell differentiation through CDC5L/ADAP1/NRD1 axis. Apoptosis : an international journal on programmed cell death 0 41663817
2026 Bi-allelic variants in NRDC cause a neurodevelopmental disorder characterized by neonatal lethality, microcephaly, and brain abnormalities. American journal of human genetics 0 41734767
2025 Comprehensive analysis of bioinformatics identification TST, SQOR and NRDC is mitochondria-related biomarkers of ischemic cerebral apoplexy. Scientific reports 0 40087350
2025 Biallelic Variant in NRDC Gene in Two Siblings With Developmental Delay and Seizures. American journal of medical genetics. Part A 0 41449824
2020 Purification and In Vitro Analysis of the Exosome Cofactors Nrd1-Nab3 and Trf4-Air2. Methods in molecular biology (Clifton, N.J.) 0 31768982

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