Affinage

AMIGO1

Amphoterin-induced protein 1 · UniProt Q86WK6

Length
493 aa
Mass
55.2 kDa
Annotated
2026-06-09
23 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/6 claims corpus-supported (83%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

AMIGO1 is a type I transmembrane leucine-rich-repeat/immunoglobulin-domain cell adhesion molecule that serves dual roles in neural circuit assembly and in shaping neuronal electrical excitability (PMID:12629050, PMID:22056818). Its ectodomain comprises six leucine-rich repeats with cysteine-rich N- and C-terminal caps followed by a C2-type Ig domain, and crystallographic and biophysical analysis shows it dimerizes through an LRR-LRR interface that is required for stable ER folding and cell-surface expression (PMID:21983541). Through homophilic LRR-mediated adhesion AMIGO1 promotes neurite extension, fasciculation, and tract formation: the substrate-bound ectodomain drives outgrowth while the soluble ectodomain acts as a dominant-negative that disrupts fasciculation in hippocampal neurons and in zebrafish fiber scaffolds (PMID:12629050, PMID:24904058), and genetic deletion in mice reveals a compartment-specific requirement for AMIGO1 in scaling retinal horizontal cell axon arbors (PMID:35169021). In parallel, AMIGO1 is an auxiliary subunit of Kv2.1/Kv2.2 voltage-gated potassium channels: it co-immunoprecipitates and colocalizes with Kv2.1, and loss of AMIGO suppresses the neuronal delayed rectifier current and reduces brain Kv2.1 protein in vivo (PMID:22056818, PMID:26240432). Assembly with Kv2 channels hyperpolarizes the activation midpoint by roughly -10 mV, and mechanistically AMIGO1 destabilizes the earliest resting conformation of the Kv2.1 voltage sensors, speeding early sensor movements and shifting the gating charge-voltage relationship to more negative voltages (PMID:34137443, PMID:35314141). The relationship is reciprocal: Kv2 α subunits are obligatory for AMIGO1 clustering, plasma-membrane trafficking, and expression, localizing it to ER-PM junctions, a dependency that extends to motor neurons where Kv2-mediated junction formation is required for AMIGO1 localization [PMID:29403353, PMID:bio_10.1101_2025.06.04.657913].

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2003 Medium

    Established AMIGO1 as an LRR/Ig adhesion molecule whose ectodomain bidirectionally controls neurite outgrowth and fasciculation, defining its first functional role in neural morphogenesis.

    Evidence Recombinant ectodomain neurite outgrowth assays and homophilic/heterophilic binding assays in hippocampal neurons

    PMID:12629050

    Open questions at the time
    • Binding partners beyond the AMIGO family not identified
    • No in vivo confirmation at this stage
    • Molecular mechanism of adhesion-to-outgrowth coupling unresolved
  2. 2011 High

    Revealed an entirely distinct function: AMIGO1 acts as an auxiliary subunit of Kv2.1, coupling the adhesion molecule to control of neuronal potassium currents.

    Evidence Reciprocal Co-IP, immunofluorescence colocalization, HEK electrophysiology, and siRNA knockdown with patch-clamp in neurons

    PMID:22056818

    Open questions at the time
    • Stoichiometry of the AMIGO1-Kv2.1 complex not defined
    • Biophysical mechanism of conductance modulation not yet resolved
    • Whether Kv2.2 is also modulated untested here
  3. 2011 High

    Determined the ectodomain structure and showed dimerization through the LRR interface is required for surface expression, providing the structural basis for both folding and adhesion.

    Evidence 2.0 Å X-ray crystallography with SAXS, static light scattering, and mutagenesis-coupled surface expression assays

    PMID:21983541

    Open questions at the time
    • Structure of full-length transmembrane protein and channel-bound complex unknown
    • Adhesion interface in trans not directly visualized
  4. 2012 Medium

    Localized AMIGO1 to dendrites and linked it to dendritic growth and apoptosis resistance, refining its compartment-specific developmental role.

    Evidence Immunofluorescence localization, siRNA knockdown with dendrite morphometry, and overexpression apoptosis assays in SH-SY5Y cells

    PMID:21938721

    Open questions at the time
    • Mechanism linking AMIGO1 to apoptosis resistance unknown
    • Signaling pathways downstream of dendritic AMIGO1 not defined
  5. 2014 Medium

    Demonstrated in vivo that homophilic AMIGO1 interactions drive fiber tract fasciculation and that AMIGO1 also regulates Kv2.1 for functional circuitry, unifying its adhesion and channel roles in a whole organism.

    Evidence Morpholino knockdown and dominant-negative ectodomain overexpression in zebrafish with fiber tract imaging and locomotion behavior

    PMID:24904058

    Open questions at the time
    • Relative contributions of adhesion vs channel functions to behavior not dissected
    • Morpholino off-target effects not fully excluded
  6. 2015 Medium

    Showed AMIGO is required in vivo for normal Kv2.1 protein levels and neuronal electrical activity, establishing the channel dependency genetically.

    Evidence AMIGO knockout mouse with Western blot for Kv2.1 and electrophysiology

    PMID:26240432

    Open questions at the time
    • Whether reduced Kv2.1 reflects trafficking or stability not resolved
    • Behavioral/circuit consequences not detailed here
  7. 2018 High

    Defined the reciprocal dependency: Kv2 α subunits are obligatory for AMIGO1 clustering and trafficking to ER-PM junctions, reframing the relationship as bidirectional control.

    Evidence Cross-species immunofluorescence, live-cell imaging in heterologous cells, and Kv2.1/Kv2.2 single and double knockout mouse analysis

    PMID:29403353

    Open questions at the time
    • Molecular interface mediating Kv2-dependent AMIGO1 clustering not mapped
    • Functional role of ER-PM junction localization for AMIGO1 unclear
  8. 2021 Medium

    Distinguished isoform-specific channel modulation, showing AMIGO1 hyperpolarizes Kv2 activation by ~-10 mV without the inactivation/deactivation slowing seen with AMIGO2.

    Evidence Voltage-clamp electrophysiology and live-cell surface trafficking imaging in heterologous cells

    PMID:34137443

    Open questions at the time
    • Structural basis of isoform-specific effects unknown
    • Native neuronal validation of -10 mV shift limited
  9. 2022 High

    Resolved the biophysical mechanism: AMIGO1 destabilizes the earliest resting state of Kv2.1 voltage sensors, explaining the hyperpolarized activation.

    Evidence Voltage-clamp, gating current measurements, and voltage-sensor toxin fluorescence spectroscopy in mammalian cells

    PMID:35314141

    Open questions at the time
    • Physical contact points between AMIGO1 and the voltage-sensor domain not identified
    • Whether this mechanism operates identically on Kv2.2 untested
  10. 2022 High

    Established a precise developmental phenotype: AMIGO1 selectively scales retinal horizontal cell axon arbors, with downstream territory matching of rod bipolar dendrites.

    Evidence Global and single-cell conditional Amigo1 knockout mice with arbor morphometry and retinal electrophysiology

    PMID:35169021

    Open questions at the time
    • Molecular signaling driving compartment-specific axon scaling unknown
    • Whether channel function contributes to this morphological role not separated
  11. 2025 Medium

    Extended the Kv2-dependency to motor neurons and linked it mechanistically to Kv2-VAP-mediated ER-PM junction formation via the Kv2.1 S590A mutant.

    Evidence Kv2.1/Kv2.2 knockout and Kv2.1 S590A knock-in mice with immunofluorescence in spinal motor neurons (preprint)

    PMID:bio_10.1101_2025.06.04.657913

    Open questions at the time
    • Preprint, single lab, not peer reviewed
    • Functional consequence of motor neuron AMIGO1 mislocalization untested
  12. 2024 Medium

    Identified an Amigo1-expressing GABAergic neuron population in the interpeduncular nucleus that mediates affective signs of nicotine withdrawal, linking AMIGO1 marker expression to circuit-level behavior.

    Evidence Chemogenetic DREADD activation of Amigo1-Cre IPN neurons with anxiety and somatic withdrawal behavioral assays (preprint)

    PMID:bio_10.1101_2024.07.05.602259

    Open questions at the time
    • Preprint, not peer reviewed
    • Whether AMIGO1 protein itself, rather than as a cell-type marker, contributes to the behavior is unaddressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How AMIGO1's adhesion/morphogenic function and its Kv2-channel auxiliary function are coordinated within single neurons, and the physical interface mediating both Kv2 binding and voltage-sensor destabilization, remain unresolved.
  • No structure of the AMIGO1-Kv2 complex
  • Contact residues for voltage-sensor modulation unmapped
  • Integration of channel vs adhesion roles in development not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 2
Partners
AMIGO1KCNB1KCNB2
Complex memberships
Kv2.1 channel complexKv2.2 channel complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 AMIGO1 (AMIGO) is a type I transmembrane protein with six leucine-rich repeats flanked by cysteine-rich LRR N- and C-terminal domains and one immunoglobulin domain; substrate-bound recombinant AMIGO ectodomain promoted neurite extension in hippocampal neurons, while soluble AMIGO ectodomain inhibited neurite fasciculation; AMIGO family members engage in homophilic and heterophilic binding with each other. Recombinant ectodomain neurite outgrowth assay in hippocampal neurons; homophilic/heterophilic binding assay between AMIGO family members The Journal of cell biology Medium 12629050
2011 AMIGO1 is an auxiliary subunit of the Kv2.1 potassium channel complex: it shows extensive spatial and temporal colocalization and co-immunoprecipitation with Kv2.1 in mouse brain, increases Kv2.1 conductance in a voltage-dependent manner in HEK cells, and siRNA-mediated inhibition of endogenous AMIGO suppresses neuronal delayed rectifier current (IK) at negative membrane voltages. Co-immunoprecipitation, immunofluorescence colocalization, electrophysiology in HEK cells, siRNA knockdown with patch-clamp in neurons EMBO reports High 22056818
2011 Crystal structure of AMIGO-1 ectodomain determined at 2.0 Å resolution, revealing a typical LRR domain with N- and C-terminal capping domains containing disulfide bridges followed by a C2-type Ig domain; AMIGO-1 forms a dimer through its LRR-LRR interface, and mutagenesis studies showed that dimerization is necessary for proper cell surface expression, suggesting a role in stable folding in the ER and cell-cell adhesion. X-ray crystallography (2.0 Å), static light scattering, SAXS, site-directed mutagenesis with cell surface expression assay Journal of molecular biology High 21983541
2012 AMIGO1 localizes predominantly to dendrites in mature primary neurons (while LRR-deleted AMIGO is axonal), and siRNA-mediated silencing of AMIGO reduces dendritic growth of cortical neurons in culture; overexpression of AMIGO in SH-SY5Y cells confers resistance to staurosporine- and H2O2-induced apoptosis. Immunofluorescence localization, siRNA knockdown with morphometric analysis of dendrites, stable overexpression with apoptosis assay Journal of cellular physiology Medium 21938721
2014 In zebrafish, amigo1 is the predominant family member expressed during nervous system development; morpholino knockdown of amigo1 impairs fasciculated tract formation in early fiber scaffolds, and mRNA-mediated overexpression of the Amigo1 ectodomain (which inhibits adhesion by the full-length protein) produces a similar defect, confirming that homophilic interactions underlie fiber tract development; Amigo1 also regulates Kv2.1 potassium channel function to form functional neural circuitry controlling locomotion. Morpholino antisense knockdown in zebrafish, mRNA overexpression of ectodomain, immunofluorescence imaging of fiber tracts, behavioral analysis The Journal of biological chemistry Medium 24904058
2015 Genetic deletion of AMIGO in mice reduces the amount of Kv2.1 channel protein in brain and alters electrophysiological properties of neurons, demonstrating that AMIGO is required for normal Kv2.1 expression levels and neuronal electrical activity in vivo. AMIGO knockout mouse, Western blot for Kv2.1 protein, electrophysiology Schizophrenia bulletin Medium 26240432
2018 In adult brain neurons, AMIGO-1 is exclusively colocalized with Kv2.1 and Kv2.2 at plasma membrane sites associated with neuronal ER:PM junctions (hypolemmal subsurface cisternae); Kv2 α subunits are obligatory for AMIGO-1 clustering, PM trafficking, and expression level—coexpression of either Kv2.1 or Kv2.2 is sufficient to drive AMIGO-1 clustering in heterologous cells, and AMIGO-1 expression/localization is lost in Kv2.1 or Kv2.2 knockout mice. Immunofluorescence colocalization across multiple mammalian species, live-cell imaging in heterologous cells, Kv2.1/Kv2.2 single and double knockout mouse analysis, subcellular fractionation/trafficking assays Frontiers in molecular neuroscience High 29403353
2021 All three AMIGO family proteins (AMIGO1, 2, 3) are controlled in surface trafficking and localization by assembly with either Kv2.1 or Kv2.2; AMIGO1 assembly with either Kv2 channel hyperpolarizes the channel activation midpoint by approximately −10 mV; AMIGO1 does not significantly slow inactivation or deactivation (unlike AMIGO2), indicating isoform-specific modulation. Electrophysiology (voltage-clamp), live-cell imaging of surface trafficking in heterologous cells, co-expression studies Journal of cell science Medium 34137443
2022 AMIGO1 modulates the Kv2.1 conductance activation pathway by destabilizing the earliest resting state of Kv2.1 voltage sensors: AMIGO1 speeds early voltage-sensor movements, shifts the gating charge-voltage (Q-V) relationship to more negative voltages, and when voltage sensors are detained at rest by toxins, AMIGO1 exerts a greater effect on the conductance-voltage relationship; fluorescence measurements from voltage-sensor toxins confirm that AMIGO1 makes the earliest resting conformation less stable upon voltage stimulation. Voltage-clamp recordings, gating current measurements, voltage-sensor toxin fluorescence spectroscopy, heterologous expression in mammalian cell lines Biophysical journal High 35314141
2022 AMIGO1 selectively promotes axon arbor growth of retinal horizontal cells; genetic deletion of Amigo1 in mice reduces horizontal cell axon arbor size without affecting horizontal cell dendrite size or synapse formation, demonstrating a compartment-specific role for AMIGO1 in axon scaling; reduction of horizontal cell axons causes territory matching-mediated shrinkage of rod bipolar cell dendrites, preserving rod bipolar pathway function. Amigo1 knockout mice, single-cell conditional knockout, morphometric analysis of axon/dendrite arbors, immunofluorescence, electrophysiological recording of retinal output The Journal of neuroscience High 35169021
2025 AMIGO-1 clustering and expression in spinal motor neurons is dependent on Kv2 subunits: AMIGO-1 clustering at ER-PM junctions is severely reduced in Kv2.1 knockout mice and moderately reduced in Kv2.2 knockout mice, and is also severely reduced in Kv2.1 S590A mutant mice that cannot bind ER VAP proteins, indicating that Kv2-mediated ER-PM junction formation is required for AMIGO-1 localization in motor neurons. Kv2.1 and Kv2.2 knockout mice, Kv2.1 S590A knock-in mutant mice, immunofluorescence colocalization in spinal motor neurons bioRxivpreprint Medium bio_10.1101_2025.06.04.657913
2024 Chemogenetic activation of Amigo1-expressing GABAergic neurons within the interpeduncular nucleus (IPN) is critical for anxiety-like behaviors in both naïve mice and those undergoing nicotine withdrawal; stimulation of Amigo1 neurons in nicotine-naïve mice elicits opposite effects on affective versus somatic signs of withdrawal, demonstrating that Amigo1-expressing IPN neurons specifically mediate the affective component of nicotine withdrawal. Chemogenetic (DREADD) activation of Amigo1-Cre targeted IPN neurons, behavioral assays for anxiety and somatic withdrawal signs bioRxivpreprint Medium bio_10.1101_2024.07.05.602259

Source papers

Stage 0 corpus · 23 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 AmiGO: online access to ontology and annotation data. Bioinformatics (Oxford, England) 1454 19033274
2003 AMIGO, a transmembrane protein implicated in axon tract development, defines a novel protein family with leucine-rich repeats. The Journal of cell biology 135 12629050
2006 AMIGO and friends: an emerging family of brain-enriched, neuronal growth modulating, type I transmembrane proteins with leucine-rich repeats (LRR) and cell adhesion molecule motifs. Brain research reviews 77 16414120
2018 Kv2 Ion Channels Determine the Expression and Localization of the Associated AMIGO-1 Cell Adhesion Molecule in Adult Brain Neurons. Frontiers in molecular neuroscience 66 29403353
2004 DEGA/AMIGO-2, a leucine-rich repeat family member, differentially expressed in human gastric adenocarcinoma: effects on ploidy, chromosomal stability, cell adhesion/migration and tumorigenicity. Oncogene 54 15107827
2017 Blood Group Antigen Matching Influence on Gestational Outcomes (AMIGO) study. Transfusion 46 28164304
2011 AMIGO is an auxiliary subunit of the Kv2.1 potassium channel. EMBO reports 42 22056818
2015 AMIGO-Kv2.1 Potassium Channel Complex Is Associated With Schizophrenia-Related Phenotypes. Schizophrenia bulletin 30 26240432
2011 Crystal structure and role of glycans and dimerization in folding of neuronal leucine-rich repeat protein AMIGO-1. Journal of molecular biology 25 21983541
2013 RamiGO: an R/Bioconductor package providing an AmiGO visualize interface. Bioinformatics (Oxford, England) 23 23297033
2004 Linkage mapping of powdery mildew and greenbug resistance genes on recombinant 1RS from 'Amigo' and 'Kavkaz' wheat-rye translocations of chromosome 1RS.1AL. Genome 22 15060581
2017 Get GO! Retrieving GO Data Using AmiGO, QuickGO, API, Files, and Tools. Methods in molecular biology (Clifton, N.J.) 21 27812941
2012 AMIGO is expressed in multiple brain cell types and may regulate dendritic growth and neuronal survival. Journal of cellular physiology 21 21938721
2013 Comparison of the safety and feasibility of arrhythmia ablation using the Amigo Robotic Remote Catheter System versus manual ablation. The American journal of cardiology 18 24440330
2016 IL-17A and TNF-α Increase the Expression of the Antiapoptotic Adhesion Molecule Amigo-2 in Arthritis Synoviocytes. Frontiers in immunology 16 27446084
1994 Chromosome painting of Amigo wheat. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 15 24178087
2021 Kv2 channel-AMIGO β-subunit assembly modulates both channel function and cell adhesion molecule surface trafficking. Journal of cell science 14 34137443
2014 Amigo adhesion protein regulates development of neural circuits in zebrafish brain. The Journal of biological chemistry 14 24904058
2022 The AMIGO1 adhesion protein activates Kv2.1 voltage sensors. Biophysical journal 10 35314141
2022 AMIGO1 Promotes Axon Growth and Territory Matching in the Retina. The Journal of neuroscience : the official journal of the Society for Neuroscience 8 35169021
1998 The pathologic cycle of the infection of the microsporidian Microgemma ovoidea (Thèl., 1895) Amigó et al. 1996 in the liver of the Red Band fish (Cepola macrophthalma L.). Parasitology research 5 9491419
2026 AMIGO - Guided assignment of 13C-methyl labelled proteins. Journal of biomolecular NMR 0 41968202
2025 A Strategy to Use Artificial MicroRNAs for Gene Silencing and Overcome (AmiGO). Methods in molecular biology (Clifton, N.J.) 0 40380067

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