TTLL3

Summary

TTLL3 (tubulin tyrosine ligase like 3, HGNC:24483) is a protein-coding gene on chromosome 3p25.3, encoding Tubulin monoglycylase TTLL3 (Q9Y4R7). Monoglycylase which modifies alpha- and beta-tubulin, adding a single glycine on the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of tubulin.

Enables protein-glycine ligase activity. Predicted to be involved in several processes, including axoneme assembly; flagellated sperm motility; and protein polyglycylation. Predicted to be located in cilium. Predicted to be active in axoneme; microtubule cytoskeleton; and sperm flagellum.

Source: NCBI Gene 26140 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 2 total
• MANE Select transcript: NM_001387446

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24483
Approved symbol	TTLL3
Name	tubulin tyrosine ligase like 3
Location	3p25.3
Locus type	gene with protein product
Status	Approved
Aliases	DKFZP434B103, HOTTL
Ensembl gene	ENSG00000214021
Ensembl biotype	protein_coding
OMIM	619195
Entrez	26140

Gene structure

Transcript identifiers

Ensembl transcripts: 36 — 21 protein_coding, 7 nonsense_mediated_decay, 7 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000310252, ENST00000383827, ENST00000414814, ENST00000417065, ENST00000418745, ENST00000419081, ENST00000422738, ENST00000426827, ENST00000426895, ENST00000427220, ENST00000430390, ENST00000430718, ENST00000430793, ENST00000431204, ENST00000438141, ENST00000438596, ENST00000439814, ENST00000443148, ENST00000452597, ENST00000452823, ENST00000455274, ENST00000459758, ENST00000466245, ENST00000471058, ENST00000473661, ENST00000474948, ENST00000482269, ENST00000483051, ENST00000492440, ENST00000493241, ENST00000496246, ENST00000496526, ENST00000602338, ENST00000685419, ENST00000703870, ENST00000715597

RefSeq mRNA: 24 — MANE Select: NM_001387446 NM_001025930, NM_001366051, NM_001387446, NM_001387447, NM_001387448, NM_001387449, NM_001387450, NM_001387451, NM_001387452, NM_001387453, NM_001387454, NM_001387455, NM_001387456, NM_001387457, NM_001387458, NM_001387459, NM_001387460, NM_001387461, NM_001387462, NM_001387463, NM_001387464, NM_001387465, NM_001387466, NM_001387467

CCDS: CCDS93199, CCDS93200

Canonical transcript exons

ENST00000685419 — 14 exons

Exon	Start	End
ENSE00001682776	9833104	9833245
ENSE00003458887	9828960	9829395
ENSE00003477249	9817645	9817759
ENSE00003481543	9826997	9827240
ENSE00003489823	9816074	9816202
ENSE00003489976	9812943	9813111
ENSE00003535627	9825800	9825948
ENSE00003550401	9810621	9810709
ENSE00003550706	9820546	9820741
ENSE00003643225	9818822	9818920
ENSE00003648275	9813248	9813345
ENSE00003663709	9834681	9834907
ENSE00003923925	9810262	9810394
ENSE00003932494	9835094	9836365

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5895 / max 597.0157, expressed in 1585 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35243	2.4235	1057
35244	2.0323	747
35241	0.9612	514
35240	0.8428	322
35242	0.3078	158
35239	0.0219	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.03	gold quality
left ovary	UBERON:0002119	98.06	gold quality
right ovary	UBERON:0002118	97.78	gold quality
endocervix	UBERON:0000458	97.73	gold quality
right testis	UBERON:0004534	97.39	gold quality
left testis	UBERON:0004533	97.33	gold quality
sural nerve	UBERON:0015488	97.24	gold quality
peripheral nervous system	UBERON:0000010	97.16	gold quality
nerve	UBERON:0001021	97.16	gold quality
tibial nerve	UBERON:0001323	97.16	gold quality
left uterine tube	UBERON:0001303	96.81	gold quality
granulocyte	CL:0000094	96.61	gold quality
mucosa of stomach	UBERON:0001199	96.60	gold quality
adenohypophysis	UBERON:0002196	96.60	gold quality
body of uterus	UBERON:0009853	96.55	gold quality
left lobe of thyroid gland	UBERON:0001120	96.10	gold quality
right lobe of thyroid gland	UBERON:0001119	96.02	gold quality
ectocervix	UBERON:0012249	96.01	gold quality
gall bladder	UBERON:0002110	95.66	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.56	gold quality
right coronary artery	UBERON:0001625	95.49	gold quality
pituitary gland	UBERON:0000007	95.20	gold quality
lower esophagus mucosa	UBERON:0035834	95.01	gold quality
skin of leg	UBERON:0001511	95.00	gold quality
thyroid gland	UBERON:0002046	94.95	gold quality
apex of heart	UBERON:0002098	94.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.91	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.91	gold quality
skin of abdomen	UBERON:0001416	94.88	gold quality
lower esophagus	UBERON:0013473	94.74	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.49
E-GEOD-70580	no	248.97

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• Characterization of another human tubulin tyrosine ligase-like gene family member (PMID:11054573)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttll3	ENSDARG00000053728
mus_musculus	Ttll3	ENSMUSG00000030276
rattus_norvegicus	Ttll3	ENSRNOG00000009032

Paralogs (12): TTLL1 (ENSG00000100271), TTLL12 (ENSG00000100304), TTLL2 (ENSG00000120440), TTLL9 (ENSG00000131044), TTLL4 (ENSG00000135912), TTLL7 (ENSG00000137941), TTLL8 (ENSG00000138892), TTLL10 (ENSG00000162571), TTLL6 (ENSG00000170703), TTLL11 (ENSG00000175764), KPRP (ENSG00000203786), TTLL13 (ENSG00000213471)

Protein

Protein identifiers

Tubulin monoglycylase TTLL3 — Q9Y4R7 (reviewed: Q9Y4R7)

Alternative names: HOTTL, Tubulin–tyrosine ligase-like protein 3

All UniProt accessions (26): A0A8I5KXU2, A0A994J3Y4, A0AAQ5BIG3, C9IZU0, C9JKU2, C9JNK2, C9JNK7, C9JQ30, C9JRM2, C9JSD3, C9JUK0, C9JW59, C9JWZ9, C9JZ73, E5RGZ6, F8WBP6, F8WD18, H0Y5E3, H3BLT7, H7C0T5, H7C197, J3KQB2, Q9Y4R7, R4GMR7, R4GMW2, R4GN12

UniProt curated annotations — full annotation on UniProt →

Function. Monoglycylase which modifies alpha- and beta-tubulin, adding a single glycine on the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of tubulin. Not involved in elongation step of the polyglycylation reaction. Preferentially glycylates a beta-tail peptide over the alpha-tail, although shifts its preference toward alpha-tail as beta-tail glutamylation increases. Competes with polyglutamylases for modification site on beta-tubulin substrate, thereby creating an anticorrelation between glycylation and glutamylation reactions. Together with TTLL8, mediates microtubule glycylation of primary and motile cilia, which is essential for their stability and maintenance. Involved in microtubule glycylation of primary cilia in colon which controls cell proliferation of epithelial cells and plays an essential role in colon cancer development. Together with TTLL8, glycylates sperm flagella which regulates axonemal dynein motor activity, thereby controlling flagellar beat, directional sperm swimming and male fertility.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Cilium. Cilium axoneme. Flagellum axoneme.

Tissue specificity. Expressed in brain, heart, kidney, testis, liver, lung, muscle, spleen, trachea and colon.

Domain organisation. Two conserved structural elements specific among monoglycylases, IS1 and IS2, are involved in glycyl chains initiation. Two conserved structural interfaces likely constitute the binding platforms for tubulin tail and microtubule. Arg-289 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.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y4R7-1	1	yes
Q9Y4R7-2	2
Q9Y4R7-5	3
Q9Y4R7-6	4

RefSeq proteins (24): NP_001021100, NP_001352980, NP_001374375, NP_001374376, NP_001374377, NP_001374378, NP_001374379, NP_001374380, NP_001374381, NP_001374382, NP_001374383, NP_001374384, NP_001374385, NP_001374386, NP_001374387, NP_001374388, NP_001374389, NP_001374390, NP_001374391, NP_001374392, NP_001374393, NP_001374394, NP_001374395, NP_001374396 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004344	TTL/TTLL_fam	Family
IPR051437	TTLL_monoglycylase	Family

Pfam: PF03133

Catalyzed reactions (Rhea), 1 shown:

• L-glutamyl-[protein] + glycine + ATP = glycyl-L-glutamyl-[protein] + ADP + phosphate + H(+) (RHEA:67180)

UniProt features (31 total): binding site 12, splice variant 6, sequence variant 6, sequence conflict 2, chain 1, domain 1, site 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4R7-F1	66.67	0.40

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 (1): 289 (essential for specifying initiation versus elongation step of the glycylase activity)

Ligand- & substrate-binding residues (12): 381; 456; 469; 469; 469; 471; 283; 289–290; 289; 321–324; 334–336; 378–379

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 125 (showing top): GOBP_MALE_GAMETE_GENERATION, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, GOBP_CILIUM_ORGANIZATION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_PEPTIDYL_GLUTAMIC_ACID_MODIFICATION, GOBP_MICROTUBULE_BUNDLE_FORMATION, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, GOMF_ACID_AMINO_ACID_LIGASE_ACTIVITY, BASAKI_YBX1_TARGETS_DN, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_AXONEME_ASSEMBLY

GO Biological Process (5): spermatogenesis (GO:0007283), flagellated sperm motility (GO:0030317), axoneme assembly (GO:0035082), cilium assembly (GO:0060271), protein modification process (GO:0036211)

GO Molecular Function (6): ATP binding (GO:0005524), metal ion binding (GO:0046872), protein-glycine ligase activity (GO:0070735), protein-glycine ligase activity, initiating (GO:0070736), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (10): cytosol (GO:0005829), microtubule (GO:0005874), cilium (GO:0005929), axoneme (GO:0005930), microtubule cytoskeleton (GO:0015630), sperm flagellum (GO:0036126), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), motile cilium (GO:0031514), 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	4
cytoskeleton	2
developmental process involved in reproduction	1
male gamete generation	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
microtubule bundle formation	1
cellular component assembly	1
cilium assembly	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
acid-amino acid ligase activity	1
catalytic activity, acting on a protein	1
protein-glycine ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound 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
9+2 motile cilium	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

514 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL3	TTLL7	Q6ZT98	596
TTLL3	RHBDL1	O75783	423
TTLL3	IFT70B	Q8N4P2	416
TTLL3	TTLL4	Q14679	401
TTLL3	UNC50	Q53HI1	399
TTLL3	C12orf54	Q6X4T0	392
TTLL3	TTLL6	Q8N841	381
TTLL3	ATAT1	Q5SQI0	373
TTLL3	MON1B	Q7L1V2	366
TTLL3	SVBP	Q8N300	366
TTLL3	AGTPBP1	Q9UPW5	364
TTLL3	FANCD2OS	Q96PS1	354
TTLL3	AGBL5	Q8NDL9	331
TTLL3	TTLL13	A6NNM8	328
TTLL3	TTLL10	Q6ZVT0	326

IntAct

4 interactions, top by confidence:

A	B	Type	Score
TTLL3	ARPC4-TTLL3	psi-mi:“MI:0915”(physical association)	0.400
CDCA5	TTLL3	psi-mi:“MI:0915”(physical association)	0.370
TTLL3	TCP1	psi-mi:“MI:0914”(association)	0.350
rpoB	TTLL3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): TTLL3 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), HSPA1L (Affinity Capture-MS), CCT3 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT6A (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT4 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), PDCL (Affinity Capture-MS), ZNHIT2 (Affinity Capture-MS), SUFU (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), SUFU (Affinity Capture-MS)

ESM2 similar proteins: A2APC3, A3KMI0, A4Q9E4, A4Q9E5, A4Q9F0, A4Q9F1, A6H8T7, A8X9V4, B2GUB3, E9P886, F7E540, H2KZM9, O48709, O75164, Q09647, Q0P4M4, Q1ECV4, Q3SXZ7, Q3SZH6, Q4R632, Q4V8A3, Q58DC8, Q5R978, Q5RD88, Q5U5Z8, Q62240, Q641W7, Q6DTM3, Q6EEF3, Q6EMB2, Q6P158, Q6P5D3, Q6ZT98, Q80TF6, Q80Z32, Q8BW72, Q8CDK2, Q8CDP0, Q8CHB8, Q8K3E5

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3905 predictions. Top by Δscore:

Variant	Effect	Δscore
3:9810189:G:GT	donor_gain	1.0000
3:9810705:TCAAG:T	donor_loss	1.0000
3:9810706:CAAGG:C	donor_loss	1.0000
3:9810707:AAGG:A	donor_loss	1.0000
3:9810708:AGGTC:A	donor_loss	1.0000
3:9810709:GGTCA:G	donor_loss	1.0000
3:9810710:G:GA	donor_loss	1.0000
3:9810711:T:G	donor_loss	1.0000
3:9812935:C:G	acceptor_gain	1.0000
3:9812936:A:AG	acceptor_gain	1.0000
3:9812937:T:G	acceptor_gain	1.0000
3:9812938:T:TA	acceptor_gain	1.0000
3:9812939:GCA:G	acceptor_loss	1.0000
3:9812940:CA:C	acceptor_loss	1.0000
3:9812941:A:AG	acceptor_gain	1.0000
3:9812941:AG:A	acceptor_loss	1.0000
3:9812942:G:GA	acceptor_gain	1.0000
3:9812942:GC:G	acceptor_gain	1.0000
3:9812942:GCA:G	acceptor_gain	1.0000
3:9812942:GCAGA:G	acceptor_gain	1.0000
3:9813107:GGATG:G	donor_gain	1.0000
3:9813108:GATG:G	donor_gain	1.0000
3:9813108:GATGG:G	donor_gain	1.0000
3:9813109:ATG:A	donor_gain	1.0000
3:9813109:ATGG:A	donor_loss	1.0000
3:9813110:TG:T	donor_gain	1.0000
3:9813110:TGGT:T	donor_loss	1.0000
3:9813111:GG:G	donor_gain	1.0000
3:9813111:GGTG:G	donor_loss	1.0000
3:9813112:G:GC	donor_loss	1.0000

AlphaMissense

5347 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000014508 (3:9816365 T>C), RS1000075445 (3:9818378 T>G), RS1000147122 (3:9819896 T>C), RS1000236905 (3:9817821 G>A,C), RS1000271691 (3:9824457 C>T), RS1000536305 (3:9818113 A>G), RS1000590819 (3:9807949 A>G), RS1000609048 (3:9823250 G>A), RS1000852254 (3:9829905 T>C), RS1000911661 (3:9835964 C>A), RS1001024474 (3:9835683 C>A,T), RS1001117819 (3:9833552 CA>C,CAA), RS1001170246 (3:9833336 C>A), RS1001273677 (3:9812595 C>G), RS1001373238 (3:9829634 A>C,G)

Disease associations

OMIM: gene MIM:619195 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
K 7174	increases expression	1
bisphenol Z	increases expression	1
bisphenol S	decreases expression, affects cotreatment	1
NSC 689534	affects binding, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Acetylglucosamine	decreases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects binding, increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Niclosamide	increases expression	1
Quercetin	increases expression	1
Smoke	increases expression	1
Theophylline	affects binding	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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