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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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TTLL6
tubulin tyrosine ligase like 6
Chromosome 17 · 17q21.32
NCBI Gene: 284076Ensembl: ENSG00000170703.16HGNC: HGNC:26664UniProt: A0AAA9X7X9
20PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingciliary basal bodyciliummicrotubule cytoskeletonToxic Nodular GoiterBarrett's esophagusmetabolic diseasehyperlipidemia
✦AI Summary

TTLL6 is a polyglutamylase enzyme that catalyzes ATP-dependent addition of polyglutamate chains to tubulin and non-tubulin proteins, preferentially targeting α-tubulin tails over β-tubulin tails 1. The enzyme employs a sophisticated quadrivalent recognition mechanism, binding to β-tubulin subunits while modifying α-tails of longitudinally adjacent dimers, and reads out existing β-tail glutamylation to create positive feedback loops that generate localized microtubule modification patterns 1. TTLL6 promotes tubulin polyglutamylation which stimulates spastin-mediated microtubule severing and is essential for ciliary structure and motility 2. In disease contexts, TTLL6 plays complex roles: it contributes to neurodegeneration when Tau missorting leads to TTLL6 mislocalization and excessive microtubule severing in Alzheimer's disease 3, while paradoxically promoting cancer cell survival by supporting mitotic spindle function 4. TTLL6 also modifies non-tubulin substrates like Mad2, regulating megakaryopoiesis 5, and shows unique microtubule-destabilizing effects among TTLL family members 6. The enzyme is expressed in various tissues including pancreatic islets and oocytes, suggesting broad physiological importance 78.

Sources cited
1
TTLL6 uses quadrivalent recognition mechanism and creates positive feedback loops for localized glutamylation patterns
PMID: 38658656
2
TTLL6 mislocalization contributes to neurodegeneration in Alzheimer's disease through excessive microtubule severing
PMID: 26691836
3
TTLL6 promotes cancer cell survival by supporting mitotic spindle function
PMID: 35333353
4
TTLL6 is essential for ciliary structure and motility through axoneme polyglutamylation
PMID: 30120249
5
TTLL6 modifies Mad2 protein and regulates megakaryopoiesis
PMID: 25332286
6
TTLL6 uniquely decreases microtubule stability among TTLL family members
PMID: 41770829
7
TTLL6 is expressed in pancreatic islets
PMID: 30956117
8
TTLL6 is expressed during human oocyte meiosis
PMID: 39920028
Disease Associationsⓘ20
Toxic Nodular GoiterOpen Targets
0.15Weak
Barrett's esophagusOpen Targets
0.08Suggestive
hyperlipidemiaOpen Targets
0.07Suggestive
metabolic diseaseOpen Targets
0.07Suggestive
essential hypertensionOpen Targets
0.06Suggestive
hypertensionOpen Targets
0.06Suggestive
esophageal adenocarcinomaOpen Targets
0.04Suggestive
maturity-onset diabetes of the young type 3Open Targets
0.04Suggestive
MODYOpen Targets
0.04Suggestive
kidney failureOpen Targets
0.04Suggestive
hypothyroidismOpen Targets
0.04Suggestive
hyperinsulinism due to INSR deficiencyOpen Targets
0.04Suggestive
3-hydroxy-3-methylglutaryl-CoA synthase deficiencyOpen Targets
0.04Suggestive
exercise-induced hyperinsulinismOpen Targets
0.04Suggestive
Glycogen storage disease due to hepatic glycogen synthase deficiencyOpen Targets
0.04Suggestive
glycogen storage disorder due to hepatic glycogen synthase deficiencyOpen Targets
0.04Suggestive
hyperproinsulinemiaOpen Targets
0.04Suggestive
hypoparathyroidism, familial isolated, 2Open Targets
0.03Suggestive
chronic kidney diseaseOpen Targets
0.03Suggestive
diabetic eye diseaseOpen Targets
0.03Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
AGBL4Protein interaction74%AGBL5Protein interaction70%TTLL13Shared pathway67%CEP41Protein interaction63%CCSER2Shared pathway33%CFAP20Shared pathway29%
Tissue Expression6 tissues
Brain
100%
Lung
44%
Ovary
16%
Liver
6%
Bone Marrow
4%
Heart
1%
Gene Interaction Network
Click a node to explore
TTLL6AGBL4AGBL5TTLL13CEP41CCSER2CFAP20
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted · UniProt Q8N841
View on AlphaFold ↗
Constraintⓘ
LOEUFⓘ
0.88LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.72 [0.59–0.88]
RankingsWhere TTLL6 stands among ~20K protein-coding genes
  • #14,309of 20,598
    Most Researched20
  • #7,778of 17,882
    Most Constrained (LOEUF)0.88
Genes detectedTTLL6
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
Structural basis for α-tubulin-specific and modification state-dependent glutamylation.
PMID: 38658656
Nat Chem Biol · 2024
1.00
2
Tau missorting and spastin-induced microtubule disruption in neurodegeneration: Alzheimer Disease and Hereditary Spastic Paraplegia.
PMID: 26691836
Mol Neurodegener · 2015
0.90
3
XBP1 variant 1 promotes mitosis of cancer cells involving upregulation of the polyglutamylase TTLL6.
PMID: 35333353
Hum Mol Genet · 2022
0.80
4
Characterization of tubulin post-translational modifications and their enzymes during human oocyte meiosis.
PMID: 39920028
Reprod Biomed Online · 2025
0.70
5
Cytosolic carboxypeptidase CCP6 is required for megakaryopoiesis by modulating Mad2 polyglutamylation.
PMID: 25332286
J Exp Med · 2014
0.60