Affinage

NALF1

NALCN channel auxiliary factor 1 · UniProt B1AL88

Length
458 aa
Mass
51.5 kDa
Annotated
2026-06-10
29 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

NALF1 (NLF-1/FAM155A) is a conserved endoplasmic reticulum protein that functions as an obligate auxiliary subunit of the NALCN sodium leak channel, governing its trafficking and the sodium leak conductance that sets neuronal resting membrane potential (PMID:23522043). First defined through its C. elegans ortholog NLF-1, the protein promotes axonal localization of NALCN channel reporters, and its loss reduces sodium leak current, hyperpolarizes premotor interneurons, and impairs rhythmic locomotion; the mouse ortholog rescues this defect, binds NALCN directly, and potentiates leak currents in cortical neurons (PMID:23522043). Robust functional reconstitution of the constitutively active, monovalent-cation-conducting NALCN channel requires co-expression of FAM155A together with UNC79 and UNC80 (PMID:32494638). Structurally, FAM155A contacts NALCN through its extracellular cysteine-rich domain, while UNC79-UNC80 form a heterodimer tethered to NALCN intracellular loops via tripartite interactions that are required for channel cell-surface localization and that relieve NALCN self-inhibition by displacing the auto-inhibitory CTD-interacting helix (PMID:33273469, PMID:35550517). Beyond its channel role, Nalf1 expression is regulated post-transcriptionally: in dorsal root ganglion neurons, the RNA-binding protein HNRNP L binds a CA-rich element (CARE) in the Nalf1 3' UTR to drive preferential translation, and disrupting HNRNP L, the CARE motif, or NALCN reduces paclitaxel-induced neuropathic pain amplification (PMID:40839605).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2013 High

    Established that NALF1 is an ER protein required for proper localization and function of the NALCN sodium leak channel, linking it causally to resting membrane potential and rhythmic behavior.

    Evidence Loss-of-function genetics, electrophysiology, reporter imaging, and behavioral assays in C. elegans, with cross-species heterologous rescue and in vitro binding plus electrophysiology for the mammalian ortholog

    PMID:23522043

    Open questions at the time
    • The structural basis of the NALF1-NALCN interaction was not defined
    • How the ER-resident protein chaperones NALCN to the axon was not resolved at the molecular level
  2. 2017 Medium

    Showed that the NALCN/NALF1 channel complex is highly stable once assembled during development, implying that NALF1 acts in channel biogenesis rather than ongoing circadian modulation.

    Evidence Temperature-inducible temporal gene expression (GAL80ts), behavioral rhythmicity, and protein persistence assays in Drosophila

    PMID:28634443

    Open questions at the time
    • Single-organism (Drosophila) finding not extended to mammalian channel turnover
    • The post-translational mechanisms that modulate the stable complex were not identified
  3. 2020 High

    Defined the minimal subunit requirements and biophysical properties of the functional NALCN complex, and resolved how FAM155A physically engages NALCN.

    Evidence Heterologous reconstitution with co-transfection and whole-cell patch clamp plus pharmacology; 2.7 Å cryo-EM structure of the rat NALCN-mouse FAM155A complex

    PMID:32494638 PMID:33273469

    Open questions at the time
    • The structure captured NALCN-FAM155A without UNC79/UNC80, leaving the full assembly mechanism unresolved
    • How FAM155A's cysteine-rich domain contributes mechanistically to trafficking versus gating was not separated
  4. 2022 High

    Resolved the full quaternary complex and the mechanism by which auxiliary subunits control NALCN surface delivery and relieve its auto-inhibition.

    Evidence Cryo-EM of the NALCN-FAM155A-UNC79-UNC80 heterotetramer with interface mutagenesis and cell surface localization assays

    PMID:35550517

    Open questions at the time
    • The dynamics of how the auto-inhibitory CIH is displaced during gating were not captured
    • FAM155A's specific contribution to relieving self-inhibition relative to UNC79-UNC80 was not isolated
  5. 2025 High

    Identified a post-transcriptional regulatory mechanism controlling NALF1 abundance in pain signaling, connecting it to neuropathic pain amplification.

    Evidence Ribosome profiling, RNA-binding protein pulldown mapping HNRNP L to a 3' UTR CARE element, and genetic knockout/CARE deletion with behavioral pain assays in mice

    PMID:40839605

    Open questions at the time
    • Whether translational control of NALF1 alters NALCN surface levels in DRG neurons was not directly shown
    • The signaling that activates HNRNP L-mediated translation upon nerve injury was not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NALF1 mechanistically couples its ER residence and cysteine-rich extracellular domain to NALCN folding, surface trafficking, and gating remains incompletely separated from the contributions of UNC79/UNC80.
  • No structure of NALF1 acting at the ER during NALCN biogenesis
  • The trafficking itinerary that delivers the complex to the axon is uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-112316 Neuronal System 2
Partners
HNRNPLNALCNUNC79UNC80
Complex memberships
NALCN-FAM155A-UNC79-UNC80 channel complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 NLF-1 (NALF1 ortholog in C. elegans) is a conserved endoplasmic reticulum (ER) protein that promotes axonal localization of all NCA (NALCN) channel reporters; loss of NLF-1 reduces sodium leak current and hyperpolarizes resting membrane potential in premotor interneurons, decreasing rhythmic locomotion initiation. Loss-of-function genetics in C. elegans, electrophysiology (sodium leak current measurement), fluorescent reporter localization, behavioral assays Neuron High 23522043
2013 Mouse NLF-1 (mNLF-1/FAM155A) functionally substitutes for C. elegans NLF-1 in vivo, physically interacts with the mammalian sodium leak channel NALCN in vitro, and potentiates sodium leak currents in primary cortical neuron cultures. Heterologous rescue in C. elegans, in vitro binding/pulldown assay, electrophysiology in primary cortical neuron cultures Neuron High 23522043
2020 Robust functional expression of NALCN in heterologous systems requires co-expression of UNC79, UNC80, and FAM155A; the resulting NALCN channel complex is constitutively active, conducts monovalent cations, is blocked by extracellular divalent cations, and is modulated by membrane voltage. Heterologous expression with co-transfection, electrophysiology (whole-cell patch clamp), pharmacological manipulation of extracellular Ca2+ Science advances High 32494638
2020 Cryo-EM structure of rat NALCN and mouse FAM155A complex at 2.7 Å resolution reveals that FAM155A contacts NALCN via its extracellular cysteine-rich domain; the non-canonical selectivity filter of NALCN dictates sodium selectivity and calcium block; asymmetric voltage sensors confer voltage modulation. Cryo-EM structure determination at 2.7 Å resolution, structure-function analysis mapping disease mutations to domain interfaces Nature communications High 33273469
2022 Cryo-EM structure of the mammalian NALCN-FAM155A-UNC79-UNC80 quaternary complex reveals that UNC79-UNC80 form a large piler-shaped heterodimer tethered to NALCN intracellular loops via tripartite interactions; two of these interactions are essential for NALCN cell surface localization; one interaction relieves NALCN self-inhibition by displacing the auto-inhibitory CTD Interacting Helix (CIH) from its binding site. Cryo-EM structure determination of heterotetrameric complex, mutagenesis of interaction interfaces, cell surface localization assays Nature communications High 35550517
2017 In Drosophila, developmental expression of Nlf-1 (NALF1 ortholog) is sufficient to promote robust rhythmic behavioral activity in adults; the NA/NALCN channel complex proteins produced during development persist in the adult brain with little decay for at least 5–7 days, indicating the channel complex is highly stable and that circadian regulation of NA channel function is mediated primarily by post-translational mechanisms independent of Nlf-1. Temperature-inducible tubulin-GAL80ts system for temporally restricted gene expression, behavioral rhythmicity assays, protein persistence assays in Drosophila head Frontiers in cellular neuroscience Medium 28634443
2025 NALF1 protein is preferentially translated (not transcriptionally upregulated) in dorsal root ganglion neurons in a mouse model of paclitaxel-induced neuropathic pain; this translational upregulation is mediated by the RNA-binding protein HNRNP L, which binds a 14-base CA-rich element (CARE) in the Nalf1 3' UTR; genetic elimination of HNRNP L, the CARE motif, or the pore-forming NALCN subunit reduces pain amplification in vivo. Ribosome profiling (functional genomics), RNA-binding protein pulldown (HNRNP L binding to CARE), genetic knockout/CARE motif deletion in mice, behavioral pain assays Pain High 40839605

Source papers

Stage 0 corpus · 29 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 The sodium leak channel, NALCN, in health and disease. Frontiers in cellular neuroscience 131 24904279
2019 Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms. Gut 95 30661054
2015 Genetic and clinical factors associated with obesity among adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort. Cancer 72 25963547
2013 NLF-1 delivers a sodium leak channel to regulate neuronal excitability and modulate rhythmic locomotion. Neuron 70 23522043
2017 Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis. Nature communications 69 28585551
2020 The NALCN channel complex is voltage sensitive and directly modulated by extracellular calcium. Science advances 55 32494638
2016 A dominant negative mutation at the ATP binding domain of AMHR2 is associated with a defective anti-Müllerian hormone signaling pathway. Molecular human reproduction 31 27430550
2022 Structure and mechanism of NALCN-FAM155A-UNC79-UNC80 channel complex. Nature communications 26 35550517
2022 Large-scale association study on daily weight gain in pigs reveals overlap of genetic factors for growth in humans. BMC genomics 19 35168569
2023 Admixture mapping implicates 13q33.3 as ancestry-of-origin locus for Alzheimer disease in Hispanic and Latino populations. HGG advances 18 37333771
2020 Structure of voltage-modulated sodium-selective NALCN-FAM155A channel complex. Nature communications 17 33273469
2019 Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma. Journal of Korean medical science 17 31099194
2024 Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages. Nature cancer 16 39478117
2023 A new neurodevelopmental disorder linked to heterozygous variants in UNC79. Genetics in medicine : official journal of the American College of Medical Genetics 15 37183800
2020 Genome-wide association study for circulating fibroblast growth factor 21 and 23. Scientific reports 14 32884031
2020 Genome-wide identification of Chiari malformation type I associated candidate genes and chromosomal variations. Turkish journal of biology = Turk biyoloji dergisi 13 33402871
2019 A biological study of supernumerary teeth derived dental pulp stem cells based on RNA-seq analysis. International endodontic journal 10 30565714
2017 The Narrow Abdomen Ion Channel Complex Is Highly Stable and Persists from Development into Adult Stages to Promote Behavioral Rhythmicity. Frontiers in cellular neuroscience 9 28634443
2020 Common variation in FAM155A is associated with diverticulitis but not diverticulosis. Scientific reports 8 32015353
2024 Genetic, epigenetic and environmental factors in diverticular disease: systematic review. BJS open 7 38831715
2022 A Genome-Wide Association Study on Abdominal Adiposity-Related Traits in Adult Korean Men. Obesity facts 7 35472719
2022 Epigenetic Differences in Long Non-coding RNA Expression in Finnish and Russian Karelia Teenagers With Contrasting Risk of Allergy and Asthma. Frontiers in allergy 6 35769561
2021 COLQ and ARHGAP15 are Associated with Diverticular Disease and are Expressed in the Colon. The Journal of surgical research 6 34225052
2023 Novel nonsense mutation in UNC80 in a Turkish patient further validates the sociable skill and severe gastrointestinal problems as part of disease spectrum. American journal of medical genetics. Part A 4 37067163
2025 A convective polymerase chain reaction (CPCR) coupled with NALF immunoassays as a rapid detection strategy for Listeria monocytogenes in pork meat. Journal of microbiological methods 3 40754009
2025 Ribosome profiling reveals that post-transcriptional control of Nalf1 by heterogeneous nuclear ribonucleoprotein L is required for paclitaxel-induced neuropathic pain. Pain 3 40839605
2024 Global A-to-I RNA editing during myogenic differentiation of goat MuSCs. Frontiers in veterinary science 2 39444736
2024 Uncovering novel pathogenic variants and pathway mutations in triple-negative breast cancer among the endogamous mizo tribe. Breast cancer research and treatment 1 39384723
2023 Differential chromatin accessibility and transcriptional dynamics define breast cancer subtypes and their lineages. bioRxiv : the preprint server for biology 1 37961519

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