Affinage

SPTBN2

Spectrin beta chain, non-erythrocytic 2 · UniProt O15020

Length
2390 aa
Mass
271.3 kDa
Annotated
2026-06-10
42 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

β-III-spectrin (SPTBN2) is a cytoskeletal scaffolding protein that links the cortical actin network to specialized membrane proteins, a role most fully characterized in cerebellar Purkinje cells where it controls neuronal excitability and survival (PMID:28173092, PMID:24603075). Its N-terminal actin-binding domain (ABD), composed of CH1 and CH2 subdomains plus an N-terminal unstructured region that becomes α-helical upon binding, engages F-actin; truncation of this N-terminal helix abolishes actin binding (PMID:29116080). Through its spectrin-repeat domains it heterodimerizes with α-II-spectrin, and through an ankyrin-binding region it recruits and maintains ankyrin-R at the dendritic plasma membrane, where the complex elevates sodium channel levels and activity and stabilizes the glutamate transporter EAAT4 (PMID:24603075, PMID:28173092). Loss of β-III-spectrin destabilizes EAAT4, producing early Purkinje cell hyperexcitability that—compounded by progressive, independent loss of the glial transporter GLAST—drives Purkinje cell death and motor decline, and is accompanied by enhanced CaMKII autophosphorylation indicative of dysregulated calcium signaling (PMID:28173092, PMID:40594196). SPTBN2 mutations cause spinocerebellar ataxia type 5 (SCA5): ABD-localized mutations such as L253P and a panel of interface mutations are thermally destabilizing and open the CH1-CH2 interface to confer pathological high-affinity actin binding, which is N-terminus–dependent and neurotoxic in vivo, whereas spectrin-repeat-domain mutations either partially uncouple or grossly disrupt the α-II/β-III-spectrin dimer, in severe and infantile-onset cases forming F-actin– and ankyrin-R–containing intracellular inclusions near the Golgi (PMID:29116080, PMID:35110634, PMID:37626910, PMID:40484375, PMID:41890131). Beyond the cerebellum, β-III-spectrin contributes to cortical neuron morphology and cognition (PMID:23236289), and acts as a membrane scaffold in non-neuronal contexts, connecting the cystine/glutamate transporter SLC7A11 to the motor protein Arp1 to suppress ferroptosis (PMID:38241838) and maintaining surface inhibitory receptors such as BTLA in T cells (PMID:41959129).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 Medium

    Established that β-III-spectrin function extends beyond the cerebellum to cortical neuron architecture and cognition, broadening the disease-relevant role of the protein.

    Evidence SPTBN2 knockout mouse with prefrontal cortex neuronal morphology analysis and object recognition testing

    PMID:23236289

    Open questions at the time
    • Molecular mechanism in cortex not dissected beyond morphology
    • No identified membrane partners in cortical neurons
  2. 2014 High

    Answered how β-III-spectrin organizes the membrane, showing it recruits and maintains ankyrin-R at Purkinje dendrites to support sodium channel function.

    Evidence Cell culture co-expression, membrane fractionation, and sodium-current electrophysiology comparing wild-type and SCA5 mutant β-III-spectrin

    PMID:24603075

    Open questions at the time
    • Direct structural basis of ankyrin-R binding not resolved
    • Sodium channel identity not specified
  3. 2016 High

    Defined the pathogenic cascade downstream of β-III-spectrin loss, distinguishing EAAT4 destabilization (early hyperexcitability) from independent GLAST loss (cell death).

    Evidence Genetic epistasis with EAAT4, GLAST, and double knockouts crossed to β-III-/- mice, with behavioral and histological readouts

    PMID:28173092

    Open questions at the time
    • Mechanism causing GLAST loss unknown
    • How EAAT4 deficiency triggers progressive degeneration not fully resolved
  4. 2017 High

    Resolved the structural mechanism of the SCA5 L253P mutation, showing it opens the CH1-CH2 interface to confer ~1000-fold higher actin affinity dependent on an N-terminal helix.

    Evidence Cryo-EM of the F-actin/ABD complex, co-sedimentation, pulsed-EPR, and N-terminal truncation mutagenesis

    PMID:29116080

    Open questions at the time
    • Cellular consequence of high-affinity binding not addressed in this study
    • Structure at modest 6.9 Å resolution
  5. 2022 High

    Linked the in vitro high-affinity actin-binding defect to disease, showing the N-terminus is required for L253P neurotoxicity in vivo.

    Evidence Drosophila pan-neuronal rescue assays with N-terminally truncated constructs plus in vitro actin binding

    PMID:35110634

    Open questions at the time
    • Drosophila model may not capture Purkinje-cell-specific pathology
    • Downstream effectors of toxicity not identified
  6. 2023 High

    Generalized the gain-of-function model by showing nine additional ABD SCA5 mutations are destabilizing and increase actin binding, establishing a shared molecular consequence.

    Evidence Thermal denaturation and actin co-sedimentation assays on nine purified mutant ABD proteins

    PMID:37626910

    Open questions at the time
    • In vivo validation of individual mutants not performed
    • Quantitative link between destabilization magnitude and disease severity unestablished
  7. 2023 Medium

    Identified SPTBN2 mRNA as a regulatory target, showing Mettl1/Wdr4 m7G methylation stabilizes the transcript and boosts translation to drive neurogenesis.

    Evidence m7G profiling, RNA stability and polysome assays, Mettl1 knockdown/overexpression in neural stem cells and an AD mouse model

    PMID:37779199

    Open questions at the time
    • Whether m7G regulation operates in adult Purkinje cells unknown
    • Direct contribution of SPTBN2 to the neurogenesis phenotype vs. other Mettl1 targets unresolved
  8. 2024 Medium

    Extended the scaffolding role to non-neuronal membranes, showing SPTBN2 connects SLC7A11 to Arp1 to maintain cystine uptake and suppress ferroptosis in cancer cells.

    Evidence Co-IP with CH-domain deletion mapping, membrane fractionation, and ferroptosis assays in NSCLC cells in vitro and in vivo

    PMID:38241838

    Open questions at the time
    • Single-lab Co-IP without reciprocal structural validation
    • Whether the same SLC7A11/Arp1 axis operates in neurons not tested
  9. 2025 High

    Distinguished molecular consequences of spectrin-repeat-domain SCA5 mutations, separating dimer uncoupling from gross complex disruption and inclusion formation.

    Evidence In vitro α-II/β-III-spectrin and actin binding assays plus cell co-expression imaging for inclusions and Golgi co-localization

    PMID:40484375

    Open questions at the time
    • Inclusion toxicity in neurons not demonstrated in vivo
    • Why infantile-onset mutations form inclusions while adult-onset T472M does not is mechanistically unexplained
  10. 2025 Medium

    Implicated dysregulated calcium signaling in pathology, showing CaMKII hyperactivation in β-III-/- mice and pharmacological rescue with T-type calcium channel inhibitors.

    Evidence CaMKII phosphorylation western blots, in vitro Purkinje cell culture with mibefradil, and gait analysis of trimethadione-treated β-III-/- mice

    PMID:40594196

    Open questions at the time
    • Causal link between scaffold loss and calcium dysregulation not mechanistically defined
    • Pharmacological benefit assessed in a single age cohort
  11. 2026 Medium

    Connected the structural actin-binding defect to physiological dysfunction in a faithful disease model, showing L253P drives β-III-spectrin redistribution, inclusions, CaMKII activation, and EAAT4 loss.

    Evidence CRISPR L253P knock-in mouse with immunofluorescence, proteomics, CaMKII western blot, EAAT4 quantification, and motor testing (preprint)

    PMID:41890131

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Causal ordering of redistribution, inclusions, and EAAT4 loss not established
  12. 2026 Medium

    Revealed an immune-cell function, placing SPTBN2 upstream of BTLA-mediated T cell exhaustion by maintaining surface inhibitory receptors.

    Evidence SPTBN2 knockout in CAR T-cells with trogocytosis, cytotoxicity, persistence assays, and BTLA re-expression rescue (preprint)

    PMID:41959129

    Open questions at the time
    • Preprint, not yet peer-reviewed
    • Whether BTLA is a direct physical partner not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How aberrant β-III-spectrin actin binding mechanistically couples to calcium/CaMKII dysregulation and progressive transporter loss, and whether its non-neuronal scaffolding functions share the same molecular logic, remains unresolved.
  • No mechanistic chain linking actin-binding gain-of-function to CaMKII activation
  • GLAST loss mechanism unknown
  • Unifying model across neuronal and non-neuronal scaffolding contexts absent

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 4 GO:0060090 molecular adaptor activity 3 GO:0005198 structural molecule activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005794 Golgi apparatus 1
Partners
ACTR1AANK1SLC1A6SLC7A11SPTAN1
Complex memberships
α-II/β-III-spectrin heterodimer

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 A SCA5 L253P missense mutation in the CH2 domain of the β-III-spectrin actin-binding domain (ABD) causes ~1000-fold increase in actin-binding affinity by opening the two CH domains (CH1 and CH2), enabling CH1 to bind actin aided by an N-terminal unstructured region that becomes α-helical upon binding. Truncation of this N-terminal helix eliminates actin binding. Cryo-EM structure at 6.9 Å of F-actin/ABD complex, co-sedimentation assays, pulsed-EPR measurements, N-terminal truncation mutagenesis Nature communications High 29116080
2022 The N-terminus of β-III-spectrin is required for high-affinity actin binding and for SCA5 neurotoxicity in vivo. N-terminal truncation eliminates L253P-induced high-affinity actin binding in vitro and rescues neurotoxicity and dendritic arborization defects caused by L253P in Drosophila neurons. Drosophila pan-neuronal expression rescue assay (loss-of-function lethality rescue and L253P neurotoxicity rescue), in vitro actin-binding assays with N-terminally truncated constructs Scientific reports High 35110634
2023 Nine additional ABD-localized SCA5 missense mutations (V58M, K61E, T62I, K65E, F160C, D255G, T271I, Y272H, H278R), all positioned at or near the CH1-CH2 interface, are thermally destabilizing and each causes increased actin-binding affinity, establishing increased actin binding as a shared molecular consequence of ABD-localized SCA5 mutations. Thermal denaturation assays, in vitro actin co-sedimentation/binding assays for nine purified mutant ABD proteins Cells High 37626910
2025 SRD-localized SCA5 mutations R480W and E532_M544del have distinct molecular consequences: E532_M544del partially uncouples complementary spectrin-repeat domains in the α-II/β-III-spectrin dimer and increases β-III-spectrin actin binding, while R480W grossly disrupts the α-II/β-III-spectrin complex and forms large intracellular inclusions containing F-actin and ankyrin-R that localize adjacent to the Golgi. Infantile-onset mutations R437W and R437Q also cause inclusions; adult-onset T472M does not. In vitro α-II/β-III-spectrin binding assays, actin co-sedimentation assays, cell co-expression imaging for inclusion formation, immunofluorescence for ankyrin-R and Golgi co-localization The Journal of biological chemistry High 40484375
2014 β-III spectrin is essential for the recruitment and maintenance of ankyrin-R at the plasma membrane of Purkinje cell dendrites. A wild-type β-III-spectrin/ankyrin-R complex increases sodium channel levels and activity in cell culture, whereas two SCA5 mutant forms of β-III-spectrin reduce ankyrin-R at the cell membrane and fail to enhance sodium currents. Cell culture co-expression, membrane fractionation to measure ankyrin-R at plasma membrane, electrophysiological recording of sodium channel currents with wild-type vs. mutant β-III-spectrin Human molecular genetics High 24603075
2016 β-III spectrin stabilizes the Purkinje cell glutamate transporter EAAT4 at the plasma membrane; loss of β-III spectrin reduces EAAT4 levels and causes early Purkinje cell hyperexcitability. Progressive subsequent loss of the glial glutamate transporter GLAST, superimposed on EAAT4 deficiency, drives Purkinje cell loss and motor decline, with posterior cerebellar Purkinje cells most vulnerable. GLAST loss is independent of EAAT4 loss. Genetic epistasis using EAAT4 knockout, GLAST knockout, and double-knockout mice crossed with β-III-/- mice; motor behavior assessment; Purkinje cell morphology and survival quantification Human molecular genetics High 28173092
2012 Loss of β-III spectrin (SPTBN2 knockout) in mice causes morphological abnormalities in prefrontal cortex neurons and deficits in object recognition, demonstrating a role for β-III spectrin in cortical brain development and cognition beyond the cerebellum. Mouse β-III spectrin knockout; neuronal morphology analysis of prefrontal cortex; object recognition behavioral testing PLoS genetics Medium 23236289
2024 SPTBN2 interacts with SLC7A11 through its CH domain and connects SLC7A11 with the motor protein Arp1, facilitating membrane localization of SLC7A11 (the System Xc- cystine/glutamate transporter). This maintains cystine uptake and glutathione synthesis, thereby suppressing ferroptosis in NSCLC cells. Co-immunoprecipitation of SPTBN2 with SLC7A11 and Arp1, CH-domain deletion mapping, membrane fractionation to assess SLC7A11 localization, ferroptosis assays in vitro and in vivo with SPTBN2 knockdown/inhibition Redox biology Medium 38241838
2026 In T cells within the tumor microenvironment, SPTBN2 maintains levels of cell-surface inhibitory proteins such as BTLA; SPTBN2 knockout in CAR T-cells protects them from trogocytosis, increases their memory state, and enhances cytotoxicity. Re-expression of BTLA largely reverses the phenotypes of SPTBN2-deficient CAR T-cells, placing SPTBN2 upstream of BTLA-mediated T cell exhaustion. SPTBN2 knockout in CAR T-cells; flow cytometry for BTLA and other surface proteins; trogocytosis assays; cytotoxicity and in vivo persistence assays; BTLA re-expression rescue experiments bioRxivpreprint Medium 41959129
2026 The SCA5 L253P knock-in mouse shows β-III-spectrin redistribution in Purkinje neurons: loss from distal dendrites, accumulation at soma/proximal dendrite plasma membrane, and formation of somatic inclusions containing F-actin and α-II-spectrin. CaMKII is ~2-fold activated and EAAT4 abundance is significantly reduced, linking aberrant actin binding to disruption of postsynaptic glutamate signaling. CRISPR knock-in mouse; immunofluorescence of β-III-spectrin subcellular distribution; elevated beam motor assay; unbiased proteomics of β-III-spectrin-associated proteins; CaMKII phosphorylation western blot; EAAT4 quantification bioRxivpreprint Medium 41890131
2025 β-III-/- (SPTBN2 knockout) mice show enhanced auto-phosphorylation of CaMKII and phosphorylation of CaMKII targets, indicating dysregulated calcium homeostasis. Mibefradil (a calcium channel inhibitor) improves disordered Purkinje cell dendritic morphology in vitro, and trimethadione (a selective T-type calcium channel inhibitor) significantly improves interlimb coordination in 8-month-old β-III-/- mice in vivo. Western blot for CaMKII phosphorylation in β-III-/- mice; in vitro Purkinje cell culture with mibefradil treatment; CatWalk XT automated gait analysis of β-III-/- mice treated with trimethadione, riluzole, or verapamil Scientific reports Medium 40594196
2023 m7G methylation of Sptbn2 mRNA by the Mettl1/Wdr4 methyltransferase complex enhances Sptbn2 mRNA stability and translation efficiency, promoting neurogenesis of neural stem cells. Silencing Mettl1 reduces SPTBN2 protein levels and impairs neuronal differentiation, while Mettl1 overexpression rescues neurogenesis in an AD mouse model. m7G methylation profiling, RNA stability assay, polysome profiling for translation efficiency, Mettl1 knockdown and overexpression in neural stem cells, in vivo hippocampal neurogenesis quantification Cell & bioscience Medium 37779199

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Recessive mutations in SPTBN2 implicate β-III spectrin in both cognitive and motor development. PLoS genetics 83 23236289
2014 In vitro antimicrobial, antioxidant and cytotoxic properties of Streptomyces lavendulae strain SCA5. BMC microbiology 49 25433533
2017 Structural basis for high-affinity actin binding revealed by a β-III-spectrin SCA5 missense mutation. Nature communications 46 29116080
2012 Genome-wide mRNA sequencing of a single canine cerebellar cortical degeneration case leads to the identification of a disease associated SPTBN2 mutation. BMC genetics 44 22781464
2024 SPTBN2 suppresses ferroptosis in NSCLC cells by facilitating SLC7A11 membrane trafficking and localization. Redox biology 35 38241838
2013 Autosomal dominant SCA5 and autosomal recessive infantile SCA are allelic conditions resulting from SPTBN2 mutations. European journal of human genetics : EJHG 35 23838597
2019 Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia. Clinical genetics 29 31066025
2013 A family with spinocerebellar ataxia type 5 found to have a novel missense mutation within a SPTBN2 spectrin repeat. Cerebellum (London, England) 28 22843192
2023 Mettl1-mediated internal m7G methylation of Sptbn2 mRNA elicits neurogenesis and anti-alzheimer's disease. Cell & bioscience 27 37779199
2021 LINC01605, regulated by the EP300-SMYD2 complex, potentiates the binding between METTL3 and SPTBN2 in colorectal cancer. Cancer cell international 27 34544413
2014 β-III spectrin underpins ankyrin R function in Purkinje cell dendritic trees: protein complex critical for sodium channel activity is impaired by SCA5-associated mutations. Human molecular genetics 27 24603075
2017 Progressive SCAR14 with unclear speech, developmental delay, tremor, and behavioral problems caused by a homozygous deletion of the SPTBN2 pleckstrin homology domain. American journal of medical genetics. Part A 21 28636205
2016 Posterior cerebellar Purkinje cells in an SCA5/SPARCA1 mouse model are especially vulnerable to the synergistic effect of loss of β-III spectrin and GLAST. Human molecular genetics 20 28173092
2014 A Japanese SCA5 family with a novel three-nucleotide in-frame deletion mutation in the SPTBN2 gene: a clinical and genetic study. Journal of human genetics 20 25142508
2015 Failure of a heterologous recombinant Sca5/OmpB protein-based vaccine to elicit effective protective immunity against Rickettsia rickettsii infections in C3H/HeN mice. Pathogens and disease 19 26519448
2021 SPTBN2 regulated by miR-424-5p promotes endometrial cancer progression via CLDN4/PI3K/AKT axis. Cell death discovery 18 34887379
2018 A Novel Homozygous Mutation in SPTBN2 Leads to Spinocerebellar Ataxia in a Consanguineous Family: Report of a New Infantile-Onset Case and Brief Review of the Literature. Cerebellum (London, England) 17 29196973
2022 CERS6-AS1 contributes to the malignant phenotypes of colorectal cancer cells by interacting with miR-15b-5p to regulate SPTBN2. The Kaohsiung journal of medical sciences 15 35146902
2021 DNA Methylation in LIME1 and SPTBN2 Genes Is Associated with Attention Deficit in Children. Children (Basel, Switzerland) 15 33572947
2021 Novel SPTBN2 gene mutation and first intragenic deletion in early onset spinocerebellar ataxia type 5. Annals of clinical and translational neurology 15 33756041
2019 Infantile-onset spinocerebellar ataxia type 5 associated with a novel SPTBN2 mutation: A case report. Brain & development 15 30898343
2021 Two novel missense variants in SPTBN2 likely associated with spinocerebellar ataxia type 5. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 12 33797620
2021 SPTBN2, a New Biomarker of Lung Adenocarcinoma. Frontiers in oncology 12 34745988
2020 Infantile Onset of Spinocerebellar Ataxia Type 5 (SCA-5) in a 6 Month Old with Ataxic Cerebral Palsy. Cerebellum (London, England) 11 31721007
1998 A transcript map of an 800-kb region on human chromosome 11q13, part of the candidate region for SCA5 and BBS1. Human genetics 9 9921902
2023 SPTBN2 regulates endometroid ovarian cancer cell proliferation, invasion and migration via ITGB4‑mediated focal adhesion and ECM receptor signalling pathway. Experimental and therapeutic medicine 7 37206547
2022 β-III-spectrin N-terminus is required for high-affinity actin binding and SCA5 neurotoxicity. Scientific reports 7 35110634
2020 A novel case of congenital spinocerebellar ataxia 5: further support for a specific phenotype associated with the p.(Arg480Trp) variant in SPTBN2. BMJ case reports 6 33318253
2007 Screening of the SPTBN2 (SCA5) gene in German SCA patients. Journal of neurology 6 17940722
2022 SPTBN2 Promotes the Progression of Thyroid Cancer by Accelerating G1/S Transition and Inhibiting Apoptosis. Disease markers 5 35968508
2023 SPTBN2 regulated by miR-214-3p inhibits the proliferation and migration of colorectal cancer cells. Cellular and molecular biology (Noisy-le-Grand, France) 4 38279463
2024 Multi-omics pan-cancer study of SPTBN2 and its value as a potential therapeutic target in pancreatic cancer. Scientific reports 3 38684762
2023 Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin. Cells 3 37626910
2025 Molecular consequences of SCA5 mutations in the spectrin-repeat domains of β-III-spectrin. The Journal of biological chemistry 2 40484375
2025 Automated gait analysis indicates efficacy of T-type calcium channel inhibition for mitigation of disrupted calcium signalling in an SCA5 mouse model. Scientific reports 2 40594196
2026 LncRNA HOXB-AS1 Accelerates Epithelial Ovarian Cancer Progression by Modulating the miR-671-5p/SPTBN2 Axis. Journal of biochemical and molecular toxicology 0 41587409
2026 A positive SPTBN2-FLI1 feedback axis promotes bladder cancer via PI3K/AKT activation. Cellular signalling 0 41791440
2026 Clinical characterization of SPTBN1, SPTBN2, and SPTBN5 variants: A case series and systematic review. Seizure 0 41819009
2026 Impaired motor activity in a CRISPR SCA5 L253P knock-in mouse is associated with selective β-III-spectrin subcellular redistribution in the cerebellum. bioRxiv : the preprint server for biology 0 41890131
2026 SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies. bioRxiv : the preprint server for biology 0 41959129
2026 Integrated multi-omics characterization of SPTBN2 overexpression reveals its pro-tumorigenic role and immune microenvironment remodeling in colorectal cancer. Frontiers in cell and developmental biology 0 42238893
2024 Molecular consequences of SCA5 mutations in the spectrin-repeat domains of β-III-spectrin. bioRxiv : the preprint server for biology 0 39345584

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