TTLL6

Summary

TTLL6 (tubulin tyrosine ligase like 6, HGNC:26664) is a protein-coding gene on chromosome 17q21.32, encoding Tubulin polyglutamylase TTLL6 (Q8N841). Polyglutamylase which modifies both tubulin and non-tubulin proteins, generating alpha-linked polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues of target proteins.

Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in microtubule bundle formation; protein polyglutamylation; and regulation of cilium beat frequency involved in ciliary motility. Predicted to act upstream of or within microtubule severing and positive regulation of cilium movement. Located in ciliary basal body.

Source: NCBI Gene 284076 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 140 total
• MANE Select transcript: NM_001130918

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26664
Approved symbol	TTLL6
Name	tubulin tyrosine ligase like 6
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ35808
Ensembl gene	ENSG00000170703
Ensembl biotype	protein_coding
OMIM	610849
Entrez	284076

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 nonsense_mediated_decay, 2 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000376681, ENST00000393382, ENST00000416950, ENST00000424018, ENST00000433608, ENST00000456415, ENST00000470462, ENST00000490027, ENST00000509809

RefSeq mRNA: 3 — MANE Select: NM_001130918 NM_001130918, NM_001366314, NM_173623

CCDS: CCDS11537, CCDS45724

Canonical transcript exons

ENST00000393382 — 16 exons

Exon	Start	End
ENSE00002039242	48816970	48817229
ENSE00003469887	48804772	48804991
ENSE00003477528	48797061	48797204
ENSE00003484731	48801525	48801643
ENSE00003493264	48799604	48799760
ENSE00003498731	48801255	48801385
ENSE00003522962	48789931	48790106
ENSE00003529608	48768989	48769254
ENSE00003561048	48787811	48787999
ENSE00003586206	48803891	48803928
ENSE00003615520	48791378	48791603
ENSE00003627433	48784923	48785201
ENSE00003641973	48786164	48786335
ENSE00003650790	48796061	48796146
ENSE00003661255	48769728	48770097
ENSE00003918848	48762234	48762973

Expression profiles

Bgee: expression breadth ubiquitous, 159 present calls, max score 92.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0473 / max 9.9239, expressed in 17 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
208236	0.0318	11
166767	0.0091	3
166764	0.0063	3

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	92.00	gold quality
right uterine tube	UBERON:0001302	90.83	gold quality
pancreatic ductal cell	CL:0002079	89.89	silver quality
right testis	UBERON:0004534	88.47	gold quality
left testis	UBERON:0004533	88.36	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.63	gold quality
testis	UBERON:0000473	85.99	gold quality
kidney epithelium	UBERON:0004819	82.93	gold quality
mucosa of transverse colon	UBERON:0004991	80.82	gold quality
bronchial epithelial cell	CL:0002328	80.80	gold quality
bronchus	UBERON:0002185	79.86	gold quality
rectum	UBERON:0001052	79.61	gold quality
ileal mucosa	UBERON:0000331	77.00	silver quality
sural nerve	UBERON:0015488	75.35	gold quality
cardiac muscle of right atrium	UBERON:0003379	74.20	gold quality
left ventricle myocardium	UBERON:0006566	74.10	gold quality
transverse colon	UBERON:0001157	72.16	gold quality
colonic mucosa	UBERON:0000317	72.14	gold quality
jejunal mucosa	UBERON:0000399	71.93	gold quality
nasal cavity epithelium	UBERON:0005384	71.85	gold quality
duodenum	UBERON:0002114	71.78	gold quality
mucosa of sigmoid colon	UBERON:0004993	70.38	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	70.15	gold quality
adult organism	UBERON:0007023	70.12	gold quality
cortex of kidney	UBERON:0001225	69.96	gold quality
fallopian tube	UBERON:0003889	68.70	gold quality
upper arm skin	UBERON:0004263	68.57	gold quality
adult mammalian kidney	UBERON:0000082	67.83	gold quality
oviduct epithelium	UBERON:0004804	67.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	67.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting TTLL6, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-7515	99.31	68.22	1795
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-3611	98.76	68.76	1290
HSA-MIR-4710	98.61	65.96	1048
HSA-MIR-6864-5P	98.38	66.59	1079

Literature-anchored findings (GeneRIF, showing 1)

• XBP1 variant 1 promotes mitosis of cancer cells involving upregulation of the polyglutamylase TTLL6. (PMID:35333353)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ttll6	ENSMUSG00000038756
rattus_norvegicus	Ttll6	ENSRNOG00000004939
drosophila_melanogaster	TTLL3B	FBGN0031853
drosophila_melanogaster	TTLL3A	FBGN0031854
drosophila_melanogaster	TTLL15	FBGN0037838
caenorhabditis_elegans		WBGENE00010630

Paralogs (12): TTLL1 (ENSG00000100271), TTLL12 (ENSG00000100304), TTLL2 (ENSG00000120440), TTLL9 (ENSG00000131044), TTLL4 (ENSG00000135912), TTLL7 (ENSG00000137941), TTLL8 (ENSG00000138892), TTLL10 (ENSG00000162571), TTLL11 (ENSG00000175764), KPRP (ENSG00000203786), TTLL13 (ENSG00000213471), TTLL3 (ENSG00000214021)

Protein

Protein identifiers

Tubulin polyglutamylase TTLL6 — Q8N841 (reviewed: Q8N841)

Alternative names: Protein polyglutamylase TTLL6, Tubulin–tyrosine ligase-like protein 6

All UniProt accessions (6): Q8N841, A0AAA9X7X9, F6QD81, F8W896, F8W9N0, F8WDP8

UniProt curated annotations — full annotation on UniProt →

Function. Polyglutamylase which modifies both tubulin and non-tubulin proteins, generating alpha-linked polyglutamate side chains on the gamma-carboxyl group of specific glutamate residues of target proteins. Preferentially mediates ATP-dependent long polyglutamate chain elongation over the initiation step of the polyglutamylation reaction. Preferentially modifies the alpha-tubulin tail over a beta-tail. Promotes tubulin polyglutamylation which stimulates spastin/SPAST-mediated microtubule severing, thereby regulating microtubule functions. Mediates microtubule polyglutamylation in primary cilia axoneme, which is important for ciliary structural formation and motility. Mediates microtubule polyglutamylation in motile cilia, necessary for the regulation of ciliary coordinated beating. Polyglutamylates non-tubulin protein nucleotidyltransferase CGAS, leading to CGAS DNA-binding inhibition, thereby preventing antiviral defense response.

Subunit / interactions. Found in a complex with CEP41.

Subcellular location. Cytoplasm. Cytoskeleton. Cilium axoneme. Cilium basal body.

Domain organisation. The flexible c-MTBD (cationic microtubule binding domain) region mediates binding to microtubules. It is positively charged and becomes ordered when bound to microtubules: it interacts with a negatively charged patch on tubulin. The presence of positive charges in the c-MTBD region is essential for proper binding. Gln-181 is the main determinant for regioselectivity, which segregates between initiases and elongases in all tubulin–tyrosine ligase family. A glutamine residue at this position is found in elongases TTLL6, TTLL9, TTLL11, TTLL13, TTLL10 and favors glutamate-chain elongation, whereas an arginine residue is found in initiases TTLL2, TTLL4, TTLL5, TTLL3, TTLL8 and favors initiation.

Similarity. Belongs to the tubulin–tyrosine ligase family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N841-1	1	yes
Q8N841-2	2
Q8N841-3	3
Q8N841-4	4

RefSeq proteins (3): NP_001124390, NP_001353243, NP_775894 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004344	TTL/TTLL_fam	Family

Pfam: PF03133

Catalyzed reactions (Rhea), 2 shown:

• L-glutamyl-[protein] + L-glutamate + ATP = gamma-L-glutamyl-L-glutamyl-[protein] + ADP + phosphate + H(+) (RHEA:60144)
• (L-glutamyl)(n)-gamma-L-glutamyl-L-glutamyl-[protein] + L-glutamate + ATP = (L-glutamyl)(n+1)-gamma-L-glutamyl-L-glutamyl-[protein] + ADP + phosphate + H(+) (RHEA:60148)

UniProt features (40 total): binding site 16, region of interest 7, splice variant 5, compositionally biased region 3, mutagenesis site 3, site 2, sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N841-F1	61.51	0.29

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 229 (essential for specifying alpha-elongation versus initiation step of the polyglutamylase activity); 411 (important for specifying alpha-elongation versus initiation step of the polyglutamylase activity)

Ligand- & substrate-binding residues (16): 223; 229–230; 229; 251–254; 264–266; 290; 312–313; 314; 315; 332; 395; 408 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
444–446	decreased binding to microtubules and polyglutamylase activity; when associated with e-464 and e-467.
464	decreased binding to microtubules and polyglutamylase activity; when associated with 396-e–e-446 and e-467.
467	decreased binding to microtubules and polyglutamylase activity; when associated with 396-e–e-446 and e-464.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8955332	Carboxyterminal post-translational modifications of tubulin

MSigDB gene sets: 105 (showing top): GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GCANCTGNY_MYOD_Q6, AREB6_01, HNF1_Q6, GOCC_MICROTUBULE_ORGANIZING_CENTER, CEBP_Q2, GOBP_CILIUM_MOVEMENT, USF_01, GOBP_REGULATION_OF_MICROTUBULE_BASED_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, HP1SITEFACTOR_Q6, TGANTCA_AP1_C, GOBP_PEPTIDYL_GLUTAMIC_ACID_MODIFICATION, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS

GO Biological Process (6): microtubule bundle formation (GO:0001578), positive regulation of cilium movement (GO:0003353), protein polyglutamylation (GO:0018095), microtubule severing (GO:0051013), regulation of cilium beat frequency involved in ciliary motility (GO:0060296), protein modification process (GO:0036211)

GO Molecular Function (10): ATP binding (GO:0005524), tubulin binding (GO:0015631), metal ion binding (GO:0046872), protein-glutamic acid ligase activity (GO:0070739), tubulin-glutamic acid ligase activity (GO:0070740), protein-glutamic acid ligase activity, initiating (GO:0106437), protein-glutamic acid ligase activity, elongating (GO:0106438), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (14): centriole (GO:0005814), cytosol (GO:0005829), microtubule (GO:0005874), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), ciliary basal body (GO:0036064), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), 9+0 non-motile cilium (GO:0097731), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
protein-glutamic acid ligase activity	3
sperm flagellum	3
microtubule cytoskeleton organization	2
microtubule organizing center	2
intracellular membraneless organelle	2
cytoskeleton	2
cilium movement	1
regulation of cilium movement	1
positive regulation of cellular process	1
peptidyl-glutamic acid modification	1
regulation of cilium beat frequency	1
regulation of cilium movement involved in cell motility	1
regulation of biological quality	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
cation binding	1
acid-amino acid ligase activity	1
catalytic activity, acting on a protein	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
microtubule	1
ciliary plasm	1
cilium	1
non-motile cilium	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL6	CEP41	Q9BYV8	860
TTLL6	AGBL4	Q5VU57	733
TTLL6	AGBL5	Q8NDL9	702
TTLL6	SPAST	Q9UBP0	542
TTLL6	TTLL5	Q6EMB2	477
TTLL6	SNX11	Q9Y5W9	471
TTLL6	TTLL10	Q6ZVT0	467
TTLL6	IFT70B	Q8N4P2	458
TTLL6	TTLL4	Q14679	438
TTLL6	TTL	Q8NG68	420
TTLL6	RNF185	Q96GF1	397
TTLL6	CGAS	Q8N884	392
TTLL6	TTLL3	Q9Y4R7	381
TTLL6	TRIM38	O00635	376
TTLL6	ARL13B	Q3SXY8	367

IntAct

5 interactions, top by confidence:

A	B	Type	Score
MAPT	TTLL6	psi-mi:“MI:0915”(physical association)	0.400
TBC1D16	CTSC	psi-mi:“MI:0914”(association)	0.350
MYH9	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
TTLL6	CRMP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (14): TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), DPYSL3 (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), TTLL6 (Affinity Capture-MS), gag-pol (Biochemical Activity), TTLL6 (Cross-Linking-MS (XL-MS)), APP (Reconstituted Complex)

ESM2 similar proteins: A0JM98, A1L1H3, A4Q9E8, A4Q9F0, A4Q9F6, A6NNM8, A7MBJ2, A8CVX7, D3ZF42, O54928, O75159, O88866, P51957, P57058, P59110, Q08D35, Q0P4M4, Q14679, Q29RN6, Q5NC05, Q5QJC4, Q5R978, Q5RHD1, Q5SUS0, Q5T7B8, Q63679, Q68UT7, Q6EEF3, Q6EMB2, Q6GQJ2, Q6IE81, Q6IE82, Q6IRU7, Q6NWW5, Q6P1H6, Q6P7W0, Q6PCM1, Q6PJP8, Q6ZPI0, Q7TP65

Diamond homologs: A2APC3, A4Q9E4, A4Q9E5, A4Q9E8, A4Q9F6, A6NNM8, A6PVC2, A8CVX7, B2GUB3, O95922, P0CAZ0, Q0VC71, Q1ECV4, Q23K29, Q23SI8, Q3SXZ7, Q3SZH6, Q4R7H0, Q564U4, Q5PPI9, Q5R978, Q641W7, Q6EEF3, Q6EMB2, Q8CHB8, Q8N841, Q91V51, Q9BWV7, Q9Y4R7, A4Q9F0, A4Q9F1, A4Q9F4, A8X9V4, E9P886, F7E540, H2KZM9, P38160, P38584, Q09647, Q14679

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

140 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	115
Likely benign	20
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3159 predictions. Top by Δscore:

Variant	Effect	Δscore
17:48769004:T:TA	donor_gain	1.0000
17:48785198:TGTA:T	acceptor_gain	1.0000
17:48785202:C:CC	acceptor_gain	1.0000
17:48786341:C:CT	acceptor_gain	1.0000
17:48787890:T:TA	donor_gain	1.0000
17:48787995:CAATC:C	acceptor_gain	1.0000
17:48787998:TC:T	acceptor_gain	1.0000
17:48787999:CC:C	acceptor_gain	1.0000
17:48787999:CCT:C	acceptor_loss	1.0000
17:48788000:C:CA	acceptor_loss	1.0000
17:48788000:C:CC	acceptor_gain	1.0000
17:48788001:T:A	acceptor_loss	1.0000
17:48789926:TGTA:T	donor_loss	1.0000
17:48789927:GTAC:G	donor_loss	1.0000
17:48789928:TACCT:T	donor_loss	1.0000
17:48789929:A:T	donor_loss	1.0000
17:48789930:C:A	donor_loss	1.0000
17:48789934:ATCT:A	donor_gain	1.0000
17:48789934:ATCTC:A	donor_gain	1.0000
17:48789935:T:C	donor_gain	1.0000
17:48789979:T:A	donor_gain	1.0000
17:48789982:T:TA	donor_gain	1.0000
17:48797055:G:C	donor_gain	1.0000
17:48797203:GG:G	acceptor_gain	1.0000
17:48797205:C:CC	acceptor_gain	1.0000
17:48804331:T:A	donor_gain	1.0000
17:48804768:TAA:T	donor_loss	1.0000
17:48804771:CCT:C	donor_gain	1.0000
17:48804782:T:TA	donor_gain	1.0000
17:48804989:CCC:C	acceptor_gain	1.0000

AlphaMissense

5932 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000016692 (17:48792050 G>A), RS1000088238 (17:48811817 C>A), RS1000189805 (17:48815625 T>G), RS1000424775 (17:48808259 C>T), RS1000425841 (17:48763656 C>A), RS1000473492 (17:48797963 C>T), RS1000517244 (17:48771865 G>A,T), RS1000527182 (17:48817131 C>T), RS1000590663 (17:48790280 G>A), RS1000640141 (17:48816918 G>A), RS1000793515 (17:48765630 A>C,G), RS1000809105 (17:48810197 C>G), RS1000864591 (17:48803207 A>T), RS1001003057 (17:48772449 T>C), RS1001190139 (17:48791706 G>T)

Disease associations

OMIM: gene MIM:610849 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006138_3	Resting-state electroencephalogram vigilance	1.000000e-06
GCST007269_165	Pulse pressure	2.000000e-17
GCST009379_209	Type 2 diabetes	3.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0005763	pulse pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases methylation, affects cotreatment, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	affects methylation	1
polyhexamethyleneguanidine	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
Vorinostat	decreases expression, affects cotreatment	1
Panobinostat	affects cotreatment, decreases expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Endosulfan	decreases expression	1
Methapyrilene	affects methylation	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.