TTLL9

Summary

TTLL9 (tubulin tyrosine ligase like 9, HGNC:16118) is a protein-coding gene on chromosome 20q11, encoding Probable tubulin polyglutamylase TTLL9 (Q3SXZ7). Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins.

Predicted to enable tubulin binding activity and tubulin-glutamic acid ligase activity. Predicted to be involved in flagellated sperm motility and microtubule cytoskeleton organization. Predicted to act upstream of or within protein polyglutamylation. Predicted to be located in cytoplasm; microtubule; and motile cilium. Predicted to be active in ciliary basal body.

Source: NCBI Gene 164395 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Moderate, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 73 total
• MANE Select transcript: NM_001008409

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16118
Approved symbol	TTLL9
Name	tubulin tyrosine ligase like 9
Location	20q11
Locus type	gene with protein product
Status	Approved
Aliases	dJ310O13.1
Ensembl gene	ENSG00000131044
Ensembl biotype	protein_coding
OMIM	619838
Entrez	164395

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 nonsense_mediated_decay, 4 protein_coding

ENST00000310998, ENST00000375921, ENST00000375922, ENST00000375934, ENST00000375938, ENST00000535842, ENST00000612972, ENST00000619753, ENST00000620043, ENST00000642230, ENST00000644596

RefSeq mRNA: 2 — MANE Select: NM_001008409 NM_001008409, NM_001367620

CCDS: CCDS42863, CCDS93027

Canonical transcript exons

ENST00000535842 — 15 exons

Exon	Start	End
ENSE00000991632	31919864	31919932
ENSE00001757814	31926049	31926091
ENSE00003496849	31939142	31939266
ENSE00003543765	31898473	31898565
ENSE00003590519	31887196	31887239
ENSE00003612330	31871122	31871195
ENSE00003622223	31934692	31934888
ENSE00003733020	31925009	31925049
ENSE00003734156	31933800	31933858
ENSE00003738953	31942945	31945000
ENSE00003747110	31909737	31909922
ENSE00003747792	31937396	31937509
ENSE00003751569	31922963	31923053
ENSE00003754718	31908591	31908702
ENSE00003925850	31870634	31870949

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 97.67.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5922 / max 25.3101, expressed in 256 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183993	0.3480	161
183992	0.2404	110
183994	0.0038	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	97.67	gold quality
bronchial epithelial cell	CL:0002328	95.87	gold quality
sperm	CL:0000019	95.23	gold quality
bronchus	UBERON:0002185	94.49	gold quality
oviduct epithelium	UBERON:0004804	90.75	gold quality
pancreatic ductal cell	CL:0002079	85.62	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	83.24	gold quality
fallopian tube	UBERON:0003889	81.77	gold quality
nasal cavity epithelium	UBERON:0005384	81.11	silver quality
mucosa of paranasal sinus	UBERON:0005030	79.85	gold quality
upper arm skin	UBERON:0004263	79.79	gold quality
left testis	UBERON:0004533	79.58	gold quality
right testis	UBERON:0004534	79.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.65	gold quality
testis	UBERON:0000473	78.21	gold quality
spinal cord	UBERON:0002240	77.23	gold quality
sural nerve	UBERON:0015488	77.08	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.99	gold quality
caudate nucleus	UBERON:0001873	75.61	gold quality
nasal cavity mucosa	UBERON:0001826	75.40	gold quality
nucleus accumbens	UBERON:0001882	75.11	gold quality
tibial nerve	UBERON:0001323	74.71	gold quality
hypothalamus	UBERON:0001898	73.68	gold quality
kidney epithelium	UBERON:0004819	73.62	gold quality
epithelium of nasopharynx	UBERON:0001951	73.32	silver quality
vena cava	UBERON:0004087	73.26	gold quality
myocardium	UBERON:0002349	73.05	gold quality
amygdala	UBERON:0001876	72.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.87	gold quality
substantia nigra	UBERON:0002038	72.42	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.41

Regulation

Is transcription factor: no

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttll9	ENSDARG00000062806
mus_musculus	Ttll9	ENSMUSG00000074673
rattus_norvegicus	Ttll9	ENSRNOG00000008596
caenorhabditis_elegans		WBGENE00044187

Paralogs (12): TTLL1 (ENSG00000100271), TTLL12 (ENSG00000100304), TTLL2 (ENSG00000120440), TTLL4 (ENSG00000135912), TTLL7 (ENSG00000137941), TTLL8 (ENSG00000138892), TTLL10 (ENSG00000162571), TTLL6 (ENSG00000170703), TTLL11 (ENSG00000175764), KPRP (ENSG00000203786), TTLL13 (ENSG00000213471), TTLL3 (ENSG00000214021)

Protein

Protein identifiers

Probable tubulin polyglutamylase TTLL9 — Q3SXZ7 (reviewed: Q3SXZ7)

Alternative names: Tubulin–tyrosine ligase-like protein 9

All UniProt accessions (8): Q3SXZ7, A0A087WWB8, A0A087WYL2, A0A087X135, A0A0A0MR21, A0A2R8Y6A5, A0A2R8YD21, B4DZ96

UniProt curated annotations — full annotation on UniProt →

Function. Probable tubulin polyglutamylase that generates side chains of glutamate on the gamma-carboxyl group of specific glutamate residues within the C-terminal tail of target proteins. Similar to TTLL1, may acquire enzymatic activity only in complex with other proteins as it is most likely lacking domains important for autonomous activity. Mediates tubulin polyglutamylation which induces establishment of microtubule heterogeneity in sperm flagella, thereby playing a role in normal motile flagella axoneme structure and sperm flagella beating pattern.

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

Domain organisation. Gln-173 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 (3)

UniProt ID	Names	Canonical?
Q3SXZ7-1	1	yes
Q3SXZ7-2	2
Q3SXZ7-3	3

RefSeq proteins (2): NP_001008409, NP_001354549 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004344	TTL/TTLL_fam	Family

Pfam: PF03133

Catalyzed reactions (Rhea), 1 shown:

• (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 (23 total): binding site 13, splice variant 5, chain 1, domain 1, site 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q3SXZ7-F1	79.64	0.49

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): 173 (essential for specifying alpha-elongation versus initiation step of the polyglutamylase activity)

Ligand- & substrate-binding residues (13): 326; 339; 339; 341; 357; 167; 173–174; 173; 211–214; 224–226; 248; 254–255 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 61 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, BENPORATH_ES_WITH_H3K27ME3, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, GOMF_ACID_AMINO_ACID_LIGASE_ACTIVITY, chr20q11, IVANOVA_HEMATOPOIESIS_EARLY_PROGENITOR, GOCC_CILIUM, GOCC_CILIARY_BASAL_BODY, GOMF_CYTOSKELETAL_PROTEIN_BINDING, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_ADENYL_NUCLEOTIDE_BINDING, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, MIKKELSEN_ES_ICP_WITH_H3K4ME3, MIKKELSEN_NPC_ICP_WITH_H3K4ME3

GO Biological Process (3): microtubule cytoskeleton organization (GO:0000226), flagellated sperm motility (GO:0030317), protein modification process (GO:0036211)

GO Molecular Function (7): ATP binding (GO:0005524), tubulin binding (GO:0015631), metal ion binding (GO:0046872), tubulin-glutamic acid ligase activity (GO:0070740), protein-glutamic acid ligase activity, elongating (GO:0106438), nucleotide binding (GO:0000166), ligase activity (GO:0016874)

GO Cellular Component (7): microtubule (GO:0005874), ciliary basal body (GO:0036064), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cilium (GO:0005929), 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
protein-glutamic acid ligase activity	2
cilium	2
cellular anatomical structure	2
cytoskeleton organization	1
microtubule-based process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
microtubule organizing center	1
intracellular anatomical structure	1
intracellular membraneless organelle	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL9	TTLL12	Q14166	665
TTLL9	RSPH1	Q8WYR4	638
TTLL9	DNAH1	Q9P2D7	554
TTLL9	TTLL5	Q6EMB2	532
TTLL9	DRC7	Q8IY82	523
TTLL9	ODAD1	Q96M63	504
TTLL9	TMEM17	Q86X19	476
TTLL9	TTLL11	Q8NHH1	462
TTLL9	CFAP97D1	B2RV13	433
TTLL9	PLA2G3	Q9NZ20	425
TTLL9	DNAJB13	P59910	421
TTLL9	B9D2	Q9BPU9	420
TTLL9	RSPH4A	Q5TD94	417
TTLL9	BPIFB6	Q8NFQ5	408
TTLL9	CCDC40	Q4G0X9	405

IntAct

4 interactions, top by confidence:

A	B	Type	Score
IFNA4	IFNA13	psi-mi:“MI:0914”(association)	0.530
TTLL9	TCP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): LACRT (Affinity Capture-MS), CCT6B (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), TTLL9 (Proximity Label-MS), CCT3 (Affinity Capture-MS), LACRT (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT6B (Affinity Capture-MS), TTLL9 (Affinity Capture-MS), CCT7 (Affinity Capture-MS), CCT2 (Affinity Capture-MS), CCT6A (Affinity Capture-MS), CCT5 (Affinity Capture-MS)

ESM2 similar proteins: A2APC3, A4Q9E4, A8X9V4, A9X4T1, B2GUB3, B2RR83, H2KZM9, O16102, O43314, O95922, P08487, P10686, P16259, P16885, P19174, P20807, P23678, P24135, P43368, P49619, P49620, P49621, P51186, Q09639, Q09647, Q0VC71, Q14562, Q14BI7, Q22070, Q23SI8, Q3SXZ7, Q3SZH6, Q564U4, Q5PPI9, Q5R746, Q5REW0, Q62077, Q641W7, Q64691, Q6NS52

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3052 predictions. Top by Δscore:

Variant	Effect	Δscore
20:31870944:GGA:G	donor_gain	1.0000
20:31870945:GA:G	donor_gain	1.0000
20:31898547:G:GT	donor_gain	1.0000
20:31898553:TGG:T	donor_gain	1.0000
20:31898554:GGA:G	donor_gain	1.0000
20:31898555:G:GT	donor_gain	1.0000
20:31898563:GGA:G	donor_gain	1.0000
20:31898564:GA:G	donor_gain	1.0000
20:31898564:GAG:G	donor_gain	1.0000
20:31898566:G:GG	donor_gain	1.0000
20:31908579:C:G	acceptor_gain	1.0000
20:31908590:GC:G	acceptor_gain	1.0000
20:31908590:GCGAA:G	acceptor_gain	1.0000
20:31908703:GT:G	donor_loss	1.0000
20:31908704:T:A	donor_loss	1.0000
20:31909727:C:A	acceptor_gain	1.0000
20:31909731:A:AG	acceptor_gain	1.0000
20:31909732:C:G	acceptor_gain	1.0000
20:31909732:CCCA:C	acceptor_loss	1.0000
20:31909733:CCA:C	acceptor_loss	1.0000
20:31909735:A:AG	acceptor_gain	1.0000
20:31909735:A:AT	acceptor_loss	1.0000
20:31909735:AGCT:A	acceptor_gain	1.0000
20:31909736:G:GT	acceptor_gain	1.0000
20:31909736:GC:G	acceptor_gain	1.0000
20:31909736:GCT:G	acceptor_gain	1.0000
20:31909736:GCTG:G	acceptor_gain	1.0000
20:31909736:GCTGA:G	acceptor_gain	1.0000
20:31909900:G:GT	donor_gain	1.0000
20:31909918:AGCCT:A	donor_gain	1.0000

AlphaMissense

2918 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:31909747:A:T	K110M	0.999
20:31909748:G:C	K110N	0.999
20:31909748:G:T	K110N	0.999
20:31909768:T:C	L117P	0.999
20:31909908:T:A	W164R	0.999
20:31909908:T:C	W164R	0.999
20:31934797:A:C	S305R	0.999
20:31934799:C:A	S305R	0.999
20:31934799:C:G	S305R	0.999
20:31934861:A:C	D326A	0.999
20:31934861:A:T	D326V	0.999
20:31908685:T:C	F101L	0.998
20:31908687:C:A	F101L	0.998
20:31908687:C:G	F101L	0.998
20:31909744:G:C	R109P	0.998
20:31909746:A:C	K110Q	0.998
20:31909746:A:G	K110E	0.998
20:31909845:T:C	F143L	0.998
20:31909847:T:A	F143L	0.998
20:31909847:T:G	F143L	0.998
20:31909919:G:C	K167N	0.998
20:31909919:G:T	K167N	0.998
20:31934806:A:C	S308R	0.998
20:31934808:T:A	S308R	0.998
20:31934808:T:G	S308R	0.998
20:31934862:C:A	D326E	0.998
20:31934862:C:G	D326E	0.998
20:31898495:T:C	F46L	0.997
20:31898497:C:A	F46L	0.997
20:31898497:C:G	F46L	0.997

dbSNP variants (sampled 300 via entrez): RS1000020646 (20:31923735 C>T), RS1000043439 (20:31936524 G>A), RS1000114797 (20:31898982 C>T), RS1000129597 (20:31891116 T>C), RS1000187151 (20:31898762 G>A), RS1000199095 (20:31943928 G>A), RS1000223653 (20:31941668 T>G), RS1000248525 (20:31917566 A>G), RS1000263617 (20:31897711 G>A,C), RS1000339478 (20:31905761 C>T), RS1000385642 (20:31929811 T>C), RS1000393663 (20:31903627 G>A,C,T), RS1000484074 (20:31897499 T>C,G), RS1000546652 (20:31942001 G>A), RS1000613623 (20:31943413 A>T)

Disease associations

OMIM: gene MIM:619838 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Moderate	Autosomal recessive

Mondo (1): (MONDO:0018393)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003030_10	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	3.000000e-06
GCST003030_9	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	4.000000e-06
GCST010703_295	Brain morphology (MOSTest)	1.000000e-14

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

7 total (human), top 7 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	increases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Clinical trials (associated diseases)

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