Affinage

MTCL1

Microtubule cross-linking factor 1 · UniProt Q9Y4B5

Length
1905 aa
Mass
209.5 kDa
Annotated
2026-06-10
26 papers in source corpus 6 papers cited in narrative 6 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MTCL1 is a non-centrosomal microtubule-crosslinking and -stabilizing protein that organizes specialized microtubule arrays in polarized cells (PMID:23902687, PMID:25366663). It functions as a parallel dimer assembled through homo-interactions of its central coiled-coil motifs and C-terminal non-coiled-coil region, with two functionally distinct microtubule-binding domains: an N-terminal domain (N-MTBD) whose adjacent first coiled-coil motif drives tight crosslinking, and a C-terminal domain (C-MTBD) that confers microtubule stabilization, where proper N-MTBD crosslinking is a prerequisite for C-MTBD-mediated stabilization (PMID:28787032). In polarizing epithelial cells, MTCL1 builds non-centrosomal apicobasal microtubule bundles and recruits PAR-1b (MARK2) to these bundles, an interaction required for their development and for columnar cell shape (PMID:23902687). At the Golgi, MTCL1 is recruited via CLASPs and AKAP450/CG-NAP, where it crosslinks and stabilizes Golgi-derived microtubules and promotes their growth, generating the stable perinuclear network that tethers the Golgi ribbon (PMID:25366663). In cerebellar Purkinje neurons, its MT-stabilizing activity maintains the stable microtubule bundles spanning the axon initial segment and the proper localization of ankyrin-G, with loss of MTCL1 causing axonal polarity defects, motor incoordination, and Purkinje cell degeneration (PMID:28283581). During mitosis MTCL1 interacts with CLASP1/2, localizes to spindle microtubules, spindle poles, and kinetochores under CDK1 phosphoregulation, and is required for faithful chromosome segregation (PMID:33587225). Its protein abundance is controlled by PP2A-PPP2R5E-mediated dephosphorylation, which protects it from proteasomal degradation (PMID:27521566).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2013 High

    Established MTCL1 as a microtubule crosslinker that builds non-centrosomal apicobasal microtubule bundles and links this activity to epithelial polarity through recruitment of PAR-1b/MARK2.

    Evidence Co-IP, MT regrowth assays, siRNA knockdown with rescue, and immunofluorescence in polarizing epithelial cells

    PMID:23902687

    Open questions at the time
    • Did not resolve the structural basis of crosslinking
    • Mechanism of how PAR-1b recruitment promotes bundle accumulation not defined
  2. 2014 High

    Defined the recruitment route and dual activities of MTCL1 at the Golgi, separating crosslinking (N-terminal) from stabilization (C-terminal) and tying it to Golgi ribbon organization.

    Evidence Co-IP with CLASPs and AKAP450/CG-NAP, siRNA knockdown with domain-dissection rescue, and microtubule dynamics assays

    PMID:25366663

    Open questions at the time
    • Direct vs indirect nature of CLASP/AKAP450 binding not fully separated
    • Quantitative contribution of Golgi-derived MTs to overall array not established
  3. 2016 Medium

    Identified PP2A-PPP2R5E as a regulator of MTCL1 stability, showing dephosphorylation protects MTCL1 from proteasomal turnover and is needed for proper microtubule organization.

    Evidence Mass spectrometry interactome, Co-IP, siRNA knockdown, and pharmacological inhibition with okadaic acid and MG132

    PMID:27521566

    Open questions at the time
    • Specific phosphosites and responsible kinase(s) not mapped
    • E3 ligase mediating degradation unknown
    • Single-lab interaction with two orthogonal approaches
  4. 2017 High

    Demonstrated an in vivo neuronal requirement: MTCL1 MT-stabilizing activity maintains AIS microtubule bundles and ankyrin-G localization, with knockout causing Purkinje degeneration and motor defects.

    Evidence In vivo shRNA knockdown with domain-specific rescue, immunofluorescence, and Mtcl1 knockout mouse behavioral and histological analysis

    PMID:28283581

    Open questions at the time
    • Molecular link between stable MT bundles and ankyrin-G scaffold retention not defined
    • Whether the same mechanism operates in non-Purkinje neurons unknown
  5. 2017 High

    Resolved the molecular architecture, showing MTCL1 acts as a parallel dimer and that N-MTBD crosslinking is a prerequisite for C-MTBD stabilization.

    Evidence In vitro MT crosslinking assays, domain dissection/mutagenesis of homo-interaction regions, and cellular validation of Golgi MT network

    PMID:28787032

    Open questions at the time
    • No high-resolution structure of MTCL1-microtubule contacts
    • How crosslinking geometry mechanistically enables stabilization not explained
  6. 2021 High

    Extended MTCL1 function to mitosis, placing it on spindle microtubules, spindle poles, and kinetochores under CDK1 control and showing a requirement for accurate chromosome segregation.

    Evidence Reciprocal Co-IP with CLASP1/2, siRNA knockdown with live-cell imaging, GFP-tagging, and immunofluorescence

    PMID:33587225

    Open questions at the time
    • CDK1 phosphosites and their functional consequences not mapped
    • Mechanism of microtubule-independent kinetochore localization unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How phosphoregulation (CDK1, PP2A) integrates with MTCL1's crosslinking/stabilization activities to coordinate its distinct interphase, neuronal, and mitotic roles remains unresolved.
  • No unified map of phosphosites controlling localization vs activity
  • No structural model of the MTCL1-microtubule complex
  • Functional interplay between Golgi, epithelial, neuronal, and mitotic pools not reconciled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005856 cytoskeleton 4 GO:0005794 Golgi apparatus 1 GO:0005815 microtubule organizing center 1
Partners
AKAP450CLASP1CLASP2MARK2PPP2R5E

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2013 MTCL1 crosslinks microtubules through its N-terminal MT-binding region and subsequent coiled-coil motifs, colocalizes with apicobasal MT bundles in polarizing epithelial cells, and its knockdown impairs development of these MT bundles and the columnar cell shape. MTCL1 recruits PAR-1b (MARK2) to apicobasal MT bundles, and the interaction with PAR-1b is required for MTCL1-dependent development of these bundles. MT regrowth assays showed MTCL1 is not required for initial radial MT growth from the apical centrosome but is essential for accumulation of non-centrosomal MTs to sublateral regions. Co-immunoprecipitation, MT regrowth assays, siRNA knockdown with rescue experiments, immunofluorescence localization Journal of cell science High 23902687
2014 MTCL1 is recruited to Golgi membranes through interactions with CLASPs and AKAP450/CG-NAP, crosslinks and stabilizes non-centrosomal Golgi-derived microtubules, and promotes microtubule growth from the Golgi membrane. Its N-terminal MT-binding region mediates crosslinking, while the C-terminal MT-binding region has a distinct microtubule-stabilizing activity. MTCL1 knockdown specifically impairs formation of the stable perinuclear microtubule network to which the Golgi ribbon tethers. Co-immunoprecipitation, siRNA knockdown, rescue experiments, immunofluorescence, microtubule dynamics assays Nature communications High 25366663
2017 In vivo knockdown of MTCL1 in cerebellar Purkinje cells causes loss of axonal polarity coupled with ankyrin-G (AnkG) mislocalization from the axon initial segment (AIS). MTCL1 lacking MT-stabilizing activity failed to restore these defects, and stable MT bundles spanning the AIS were disorganized in knockdown cells. MTCL1 colocalizes with stable MT bundles at the axon hillock and proximal axon during early postnatal development. Mtcl1 gene disruption in mice results in abnormal motor coordination with Purkinje cell degeneration. In vivo shRNA knockdown in Purkinje cells, rescue with MT-stabilizing domain mutant, immunofluorescence, Mtcl1 knockout mouse model with behavioral and histological analysis The EMBO journal High 28283581
2017 MTCL1 forms a parallel dimer through multiple homo-interactions of central coiled-coil motifs and the most C-terminal non-coiled-coil region. The first coiled-coil motif adjacent to N-MTBD is sufficient for MT crosslinking without affecting MT dynamics; disruption of this motif transforms MTCL1-induced MT assembly from tight to network-like bundles. The MT-stabilizing activity is completely attributed to the C-terminal MT-binding domain (C-MTBD), and normal crosslinking by N-MTBD is required for microtubule stabilization by C-MTBD. Suppression of the first coiled-coil homo-interaction inhibited endogenous MTCL1 function to stabilize Golgi-associated microtubules. In vitro MT crosslinking assays, domain dissection/mutagenesis, structure-function analysis of homo-interaction regions, immunofluorescence of Golgi MT network PloS one High 28787032
2016 PPP2R5E, a regulatory subunit of protein phosphatase 2A (PP2A), interacts with MTCL1 and regulates its protein abundance. Depletion of PPP2R5E reduced MTCL1 abundance; exogenous PPP2R5E expression increased endogenous MTCL1. Inhibition of phosphatase activity by okadaic acid reduced MTCL1, which was restored by the proteasome inhibitor MG132, indicating PP2A-mediated phosphorylation protects MTCL1 from proteasomal degradation. Cells depleted of PPP2R5E and MTCL1 exhibited defects in microtubule organization. Mass spectrometry interactome screen, Co-immunoprecipitation, siRNA knockdown, pharmacological inhibition (okadaic acid, MG132), immunofluorescence The FEBS journal Medium 27521566
2021 SOGA2/MTCL1 interacts with CLASP1 and CLASP2 during mitosis (confirmed by reciprocal Co-IP with specific antibodies), is phospho-regulated during mitosis by CDK1, co-localizes with mitotic spindle microtubules and spindle poles throughout mitosis, and shows microtubule-independent localization at kinetochores by GFP-tagging. SOGA2/MTCL1 is independently required for faithful chromosome segregation, and both SOGA1 and SOGA2/MTCL1 are enriched at the midbody during cytokinesis. Reciprocal Co-immunoprecipitation with specific polyclonal antibodies, siRNA knockdown with live-cell imaging, immunofluorescence, GFP-tagging and fluorescence microscopy Chromosome research High 33587225

Source papers

Stage 0 corpus · 26 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2022 Circular RNA MTCL1 promotes advanced laryngeal squamous cell carcinoma progression by inhibiting C1QBP ubiquitin degradation and mediating beta-catenin activation. Molecular cancer 77 35366893
2012 Genome-wide association uncovers shared genetic effects among personality traits and mood states. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 68 22628180
2017 MTCL1 plays an essential role in maintaining Purkinje neuron axon initial segment. The EMBO journal 42 28283581
2014 MTCL1 crosslinks and stabilizes non-centrosomal microtubules on the Golgi membrane. Nature communications 31 25366663
2017 Large-scale exploratory genetic analysis of cognitive impairment in Parkinson's disease. Neurobiology of aging 27 28526295
2013 The novel PAR-1-binding protein MTCL1 has crucial roles in organizing microtubules in polarizing epithelial cells. Journal of cell science 25 23902687
2019 Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria. International journal of cancer 21 31173346
2020 Homozygosity mapping and next generation sequencing for the genetic diagnosis of hereditary ataxia and spastic paraplegia in consanguineous families. Parkinsonism & related disorders 13 32961396
2019 A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene. Clinical genetics 12 30548255
2015 A pilot genome-wide association study of breast cancer susceptibility loci in Indonesia. Asian Pacific journal of cancer prevention : APJCP 12 25824743
2023 Jaw1/LRMP is associated with the maintenance of Golgi ribbon structure. Journal of biochemistry 11 36689741
2023 Mucosal expression of PI3, ANXA1, and VDR discriminates Crohn's disease from ulcerative colitis. Scientific reports 11 37891214
2018 The transcriptional response of mouse spleen B cells to IL-4: Comparison to the response of human peripheral blood B cells. Biochemistry and biophysics reports 10 30302405
2016 A regulatory subunit of protein phosphatase 2A, PPP2R5E, regulates the abundance of microtubule crosslinking factor 1. The FEBS journal 10 27521566
2009 Mutations in genes encoding sorting nexins alter production of intracellular and extracellular proteases in Aspergillus nidulans. Genetics 8 19204378
2024 Co-Colorectal cancer stem cells employ the FADS1/DDA axis to evade NK cell-mediated immunosuppression after co-cultured with NK cells under hypoxia. International immunopharmacology 5 39488917
2022 MTCL2 promotes asymmetric microtubule organization by crosslinking microtubules on the Golgi membrane. Journal of cell science 5 35543016
2021 SOGA1 and SOGA2/MTCL1 are CLASP-interacting proteins required for faithful chromosome segregation in human cells. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 5 33587225
2025 Genetic differences between primary colorectal cancer and its paired synchronous and metachronous metastases. International journal of cancer 4 40884237
2017 Molecular basis of the microtubule-regulating activity of microtubule crosslinking factor 1. PloS one 4 28787032
2024 Hsa_circ_0000825 promotes the progression of laryngeal squamous cell carcinoma by sponging miR-766 and interacting with ELAVL1. Heliyon 3 39319166
2023 Circular RNA MTCL1 targets SMAD3 by sponging miR-145-5p for regulation of cell proliferation and migration in Hirschsprung's disease. Pediatric surgery international 3 38127107
2022 Whole Exome Sequencing Study in Isolated South-Eastern Moravia (Czechia) Population Indicates Heterogenous Genetic Background for Parkinsonism Development. Frontiers in neuroscience 3 35368288
2022 Circular RNA circ-ABCB10 Promotes Proliferation and Inhibits Apoptosis of Laryngeal Carcinoma by Inhibiting KLF6. Computational and mathematical methods in medicine 2 35756421
2024 Comprehensive Analysis of Crucial m6A-Related Differentially Expressed Genes in Psoriasis. Frontiers in bioscience (Landmark edition) 1 39344312
2026 Integrating sequence-based GWAS and comparative genomic analysis reveals conservation and species-specificity of putative functional variants influencing tail length and tail abnormalities in pigs and sheep. PloS one 0 41774747

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