TTLL2

Summary

TTLL2 (tubulin tyrosine ligase like 2, HGNC:21211) is a protein-coding gene on chromosome 6q27, encoding Probable tubulin polyglutamylase TTLL2 (Q9BWV7). 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 microtubule cytoskeleton organization. Predicted to be active in ciliary basal body.

Source: NCBI Gene 83887 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 109 total
• MANE Select transcript: NM_031949

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21211
Approved symbol	TTLL2
Name	tubulin tyrosine ligase like 2
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	NYD-TSPG, dJ366N23.3
Ensembl gene	ENSG00000120440
Ensembl biotype	protein_coding
Entrez	83887

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 nonsense_mediated_decay

ENST00000239587, ENST00000512917, ENST00000515138, ENST00000649884

RefSeq mRNA: 2 — MANE Select: NM_031949 NM_001410948, NM_031949

CCDS: CCDS5301, CCDS94032

Canonical transcript exons

ENST00000239587 — 3 exons

Exon	Start	End
ENSE00000815363	167340105	167342688
ENSE00000894424	167338647	167338803
ENSE00002046986	167325086	167325220

Expression profiles

Bgee: expression breadth broad, 89 present calls, max score 86.58.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1045 / max 115.4778, expressed in 4 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
71200	0.0950	4
71199	0.0095	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	86.58	gold quality
left testis	UBERON:0004533	82.42	gold quality
right testis	UBERON:0004534	81.19	gold quality
testis	UBERON:0000473	80.01	gold quality
upper arm skin	UBERON:0004263	65.13	gold quality
right lobe of liver	UBERON:0001114	62.90	gold quality
cortical plate	UBERON:0005343	61.60	gold quality
adult organism	UBERON:0007023	61.14	gold quality
ventricular zone	UBERON:0003053	57.74	gold quality
ileal mucosa	UBERON:0000331	56.66	silver quality
ganglionic eminence	UBERON:0004023	56.45	gold quality
buccal mucosa cell	CL:0002336	55.35	gold quality
mucosa of transverse colon	UBERON:0004991	55.30	gold quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
left ventricle myocardium	UBERON:0006566	54.23	gold quality
transverse colon	UBERON:0001157	54.07	gold quality
liver	UBERON:0002107	53.98	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
epithelial cell of pancreas	CL:0000083	53.59	gold quality
tendon of biceps brachii	UBERON:0008188	53.37	gold quality
tibialis anterior	UBERON:0001385	52.05	silver quality
rectum	UBERON:0001052	51.49	gold quality
muscle layer of sigmoid colon	UBERON:0035805	51.40	gold quality
pancreatic ductal cell	CL:0002079	51.24	silver quality
colon	UBERON:0001155	50.33	gold quality
myocardium	UBERON:0002349	50.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	50.03	gold quality
large intestine	UBERON:0000059	50.00	gold quality
intestine	UBERON:0000160	49.57	gold quality
small intestine	UBERON:0002108	49.01	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.44

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting TTLL2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-501-5P	98.77	68.88	1328
HSA-MIR-500A-5P	98.76	69.13	1241
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-3151-3P	97.80	66.16	479

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	ttll2	ENSDARG00000077853
mus_musculus	Ttll2	ENSMUSG00000079722
rattus_norvegicus	Ttll2	ENSRNOG00000033901

Paralogs (12): TTLL1 (ENSG00000100271), TTLL12 (ENSG00000100304), TTLL9 (ENSG00000131044), TTLL4 (ENSG00000135912), TTLL7 (ENSG00000137941), TTLL8 (ENSG00000138892), TTLL10 (ENSG00000162571), TTLL6 (ENSG00000170703), TTLL11 (ENSG00000175764), KPRP (ENSG00000203786), TTLL13 (ENSG00000213471), TTLL3 (ENSG00000214021)

Protein

Protein identifiers

Probable tubulin polyglutamylase TTLL2 — Q9BWV7 (reviewed: Q9BWV7)

Alternative names: Testis-specific protein NYD-TSPG, Tubulin–tyrosine ligase-like protein 2

All UniProt accessions (3): A0A3B3IRU1, D6R9R4, Q9BWV7

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. Probably involved in the side-chain initiation step of the polyglutamylation reaction rather than the elongation step.

Tissue specificity. Testis.

Domain organisation. Arg-218 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.

RefSeq proteins (2): NP_001397877, NP_114155* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004344	TTL/TTLL_fam	Family

Pfam: PF03133

UniProt features (31 total): binding site 14, sequence variant 10, region of interest 2, chain 1, domain 1, site 1, sequence conflict 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BWV7-F1	72.63	0.53

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): 218 (essential for specifying initiation versus elongation step of the polyglutamylase activity)

Ligand- & substrate-binding residues (14): 279; 298–299; 301; 321; 373; 386; 386; 388; 404; 212; 218–219; 218 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 50 (showing top): GOCC_MICROTUBULE_ORGANIZING_CENTER, MODULE_171, MODULE_301, GOMF_LIGASE_ACTIVITY_FORMING_CARBON_NITROGEN_BONDS, GOMF_ACID_AMINO_ACID_LIGASE_ACTIVITY, MODULE_188, chr6q27, GOCC_CILIUM, GOCC_CILIARY_BASAL_BODY, GOMF_CYTOSKELETAL_PROTEIN_BINDING, GOMF_ADENYL_NUCLEOTIDE_BINDING, MODULE_49, MODULE_292, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_MICROTUBULE_CYTOSKELETON_ORGANIZATION

GO Biological Process (2): microtubule cytoskeleton organization (GO:0000226), 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), nucleotide binding (GO:0000166), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (1): ciliary basal body (GO:0036064)

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
cytoskeleton organization	1
microtubule-based process	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
cation binding	1
protein-glutamic acid ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
microtubule organizing center	1
cilium	1

Protein interactions and networks

STRING

592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL2	DMXL1	Q9Y485	506
TTLL2	COX7B2	Q8TF08	497
TTLL2	GARIN5B	Q8N5Q1	479
TTLL2	GPR153	Q6NV75	474
TTLL2	RHBDL1	O75783	469
TTLL2	PLEKHG1	Q9ULL1	467
TTLL2	CCDC187	A0A096LP49	454
TTLL2	TMCO2	Q7Z6W1	454
TTLL2	Q12799	Q12799	446
TTLL2	BCAS3	Q9H6U6	440
TTLL2	ADSL	P30566	436
TTLL2	CCDC54	Q8NEL0	436
TTLL2	PACSIN1	Q9BY11	433
TTLL2	FAM209A	Q5JX71	423
TTLL2	C6orf118	Q5T5N4	419

IntAct

3 interactions, top by confidence:

A	B	Type	Score
TTLL2	HERC3	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (3): HERC3 (Affinity Capture-MS), TTLL2 (Affinity Capture-MS), HERC3 (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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	94
Likely benign	10
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

482 predictions. Top by Δscore:

Variant	Effect	Δscore
6:167325218:GGG:G	donor_gain	0.9900
6:167325219:GG:G	donor_gain	0.9900
6:167325219:GGG:G	donor_gain	0.9900
6:167325220:GG:G	donor_gain	0.9900
6:167325222:T:TC	donor_loss	0.9900
6:167340099:TTTTA:T	acceptor_loss	0.9900
6:167340100:TTTAG:T	acceptor_loss	0.9900
6:167340101:TTAG:T	acceptor_loss	0.9900
6:167340103:A:AG	acceptor_gain	0.9900
6:167340104:G:GG	acceptor_gain	0.9900
6:167340104:GA:G	acceptor_gain	0.9900
6:167340104:GAAA:G	acceptor_gain	0.9900
6:167340104:GAAAA:G	acceptor_gain	0.9900
6:167325221:G:GG	donor_gain	0.9800
6:167328075:A:T	donor_gain	0.9800
6:167340104:GAA:G	acceptor_gain	0.9800
6:167339438:G:GG	donor_gain	0.9700
6:167340098:T:G	acceptor_gain	0.9700
6:167339397:TTCAA:T	donor_gain	0.9600
6:167339393:G:GT	donor_gain	0.9500
6:167339444:C:T	donor_gain	0.9500
6:167340091:T:TA	acceptor_gain	0.9500
6:167336267:GT:G	donor_gain	0.9400
6:167340097:A:AG	acceptor_gain	0.9400
6:167338744:G:GT	donor_gain	0.9300
6:167339815:G:GG	donor_gain	0.9200
6:167325225:GC:G	donor_gain	0.9100
6:167340089:AAT:A	acceptor_gain	0.9100
6:167325213:GCGC:G	donor_gain	0.9000
6:167325181:G:GT	donor_gain	0.8500

AlphaMissense

3934 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:167340367:A:T	K156I	0.995
6:167340536:G:C	K212N	0.994
6:167340536:G:T	K212N	0.994
6:167340165:T:C	F89L	0.989
6:167340167:T:A	F89L	0.989
6:167340167:T:G	F89L	0.989
6:167340863:A:C	K321N	0.989
6:167340863:A:T	K321N	0.989
6:167340659:A:C	K253N	0.988
6:167340659:A:T	K253N	0.988
6:167341018:A:T	D373V	0.987
6:167341018:A:C	D373A	0.986
6:167340368:A:C	K156N	0.984
6:167340368:A:T	K156N	0.984
6:167340753:T:C	F285L	0.983
6:167340755:T:A	F285L	0.983
6:167340755:T:G	F285L	0.983
6:167341112:G:C	K404N	0.982
6:167341112:G:T	K404N	0.982
6:167340444:T:C	F182L	0.981
6:167340446:C:A	F182L	0.981
6:167340446:C:G	F182L	0.981
6:167340535:A:C	K212T	0.981
6:167341019:T:A	D373E	0.981
6:167341019:T:G	D373E	0.981
6:167340862:A:T	K321I	0.979
6:167340657:A:G	K253E	0.977
6:167340739:T:C	F280S	0.977
6:167340742:C:A	A281D	0.977
6:167340797:C:A	N299K	0.977

dbSNP variants (sampled 300 via entrez): RS1000102585 (6:167331774 C>T), RS1000620193 (6:167335633 A>C), RS1000632454 (6:167327449 C>G), RS1001158993 (6:167331019 G>C), RS1001424110 (6:167340062 G>C), RS1001673547 (6:167325598 C>T), RS1001898173 (6:167339757 T>A), RS1001936132 (6:167328129 T>C), RS1002073719 (6:167328371 G>A), RS1002125577 (6:167325362 T>C), RS1002411907 (6:167326717 A>G), RS1002542773 (6:167323205 A>G), RS1002720516 (6:167324379 A>C,G), RS1002919803 (6:167343142 A>G), RS1003079422 (6:167324568 C>T)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003901_15	Cognitive decline (age-related)	4.000000e-06
GCST006618_4	Uterine fibroid size (maximum dimension)	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009410	uterine fibroid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Copper	affects cotreatment, decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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