TTLL8

Summary

TTLL8 (tubulin tyrosine ligase like 8, HGNC:34000) is a protein-coding gene on chromosome 22q13.33, encoding Protein monoglycylase TTLL8 (A6PVC2). Monoglycylase which modifies both tubulin and non-tubulin proteins, adding a single glycine to the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of target proteins.

Predicted to enable protein-glycine ligase activity, initiating. Predicted to be involved in several processes, including axoneme assembly; flagellated sperm motility; and protein polyglycylation. Predicted to act upstream of or within cilium assembly. Predicted to be located in cilium. Predicted to be active in axoneme; microtubule cytoskeleton; and sperm flagellum.

Source: NCBI Gene 164714 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 3 total
• MANE Select transcript: NM_001350317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34000
Approved symbol	TTLL8
Name	tubulin tyrosine ligase like 8
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000138892
Ensembl biotype	protein_coding
OMIM	619193
Entrez	164714

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000433387, ENST00000477219

RefSeq mRNA: 1 — MANE Select: NM_001350317 NM_001350317

CCDS: CCDS93183

Canonical transcript exons

ENST00000433387 — 14 exons

Exon	Start	End
ENSE00000935803	50033202	50033445
ENSE00000935804	50031686	50032109
ENSE00001291365	50041621	50041807
ENSE00001327607	50045856	50045970
ENSE00001366757	50030430	50030925
ENSE00001375695	50045255	50045389
ENSE00001376558	50050109	50050247
ENSE00001381515	50055234	50055325
ENSE00001383828	50047168	50047296
ENSE00001628946	50034357	50034505
ENSE00001778004	50056869	50056973
ENSE00003690167	50049249	50049322
ENSE00003977023	50018575	50018791
ENSE00003977272	50058154	50058298

Expression profiles

Bgee: expression breadth broad, 44 present calls, max score 97.83.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	97.83	gold quality
right testis	UBERON:0004534	72.62	gold quality
left testis	UBERON:0004533	71.70	gold quality
testis	UBERON:0000473	71.48	gold quality
bone marrow cell	CL:0002092	43.85	gold quality
sural nerve	UBERON:0015488	40.62	gold quality
vermiform appendix	UBERON:0001154	40.31	gold quality
tonsil	UBERON:0002372	38.94	gold quality
lymph node	UBERON:0000029	38.50	gold quality
bone marrow	UBERON:0002371	37.93	gold quality
lower esophagus mucosa	UBERON:0035834	37.22	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
skeletal muscle tissue	UBERON:0001134	34.74	gold quality
monocyte	CL:0000576	33.77	gold quality
leukocyte	CL:0000738	33.21	gold quality
muscle tissue	UBERON:0002385	33.17	gold quality
duodenum	UBERON:0002114	32.50	gold quality
prefrontal cortex	UBERON:0000451	32.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
mucosa of stomach	UBERON:0001199	31.81	gold quality
left uterine tube	UBERON:0001303	30.70	gold quality
liver	UBERON:0002107	30.44	gold quality
caudate nucleus	UBERON:0001873	30.43	silver quality
fundus of stomach	UBERON:0001160	30.34	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
frontal cortex	UBERON:0001870	29.87	gold quality
superior frontal gyrus	UBERON:0002661	29.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttll6	ENSDARG00000054023
mus_musculus	Ttll8	ENSMUSG00000022388
rattus_norvegicus	Ttll8	ENSRNOG00000032311
drosophila_melanogaster	TTLL3B	FBGN0031853
drosophila_melanogaster	TTLL3A	FBGN0031854
drosophila_melanogaster	TTLL15	FBGN0037838
drosophila_melanogaster	TTLL6B	FBGN0039501
caenorhabditis_elegans		WBGENE00010630

Paralogs (12): TTLL1 (ENSG00000100271), TTLL12 (ENSG00000100304), TTLL2 (ENSG00000120440), TTLL9 (ENSG00000131044), TTLL4 (ENSG00000135912), TTLL7 (ENSG00000137941), TTLL10 (ENSG00000162571), TTLL6 (ENSG00000170703), TTLL11 (ENSG00000175764), KPRP (ENSG00000203786), TTLL13 (ENSG00000213471), TTLL3 (ENSG00000214021)

Protein

Protein identifiers

Protein monoglycylase TTLL8 — A6PVC2 (reviewed: A6PVC2)

Alternative names: Tubulin–tyrosine ligase-like protein 8

All UniProt accessions (1): A0A1C7CYW9

UniProt curated annotations — full annotation on UniProt →

Function. Monoglycylase which modifies both tubulin and non-tubulin proteins, adding a single glycine to the gamma-carboxyl groups of specific glutamate residues to generate monoglycine side chains within the C-terminal tail of target proteins. Not involved in elongation step of the polyglycylation reaction. Preferentially monoglycylates alpha-tubulin over beta-tubulin. Together with TTLL3, mediates microtubule glycylation of primary and motile cilia, which is essential for their stability and maintenance. Together with TTLL3, glycylates sperm flagella which regulates axonemal dynein motor activity, thereby controlling flagellar beat, directional sperm swimming and male fertility. Monoglycylates non-tubulin proteins such as ANP32A, ANP32B, SET, NCL and NAP1.

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

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-360 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 (2)

UniProt ID	Names	Canonical?
A6PVC2-1	1	yes
A6PVC2-2	2

RefSeq proteins (1): NP_001337246* (*=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 (23 total): binding site 11, splice variant 3, region of interest 3, sequence variant 3, chain 1, domain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6PVC2-F1	70.64	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): 360 (essential for specifying initiation versus elongation step of the glycylase activity)

Ligand- & substrate-binding residues (11): 449–450; 527; 540; 540; 540; 542; 354; 360–361; 360; 392–395; 405–407

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 56 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_UP, GOBP_MALE_GAMETE_GENERATION, NIKOLSKY_BREAST_CANCER_22Q13_AMPLICON, 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, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_CELL_PROJECTION_ORGANIZATION, GOBP_AXONEME_ASSEMBLY, GOCC_CYTOPLASMIC_REGION

GO Biological Process (6): spermatogenesis (GO:0007283), protein polyglycylation (GO:0018094), flagellated sperm motility (GO:0030317), axoneme assembly (GO:0035082), protein modification process (GO:0036211), cilium assembly (GO:0060271)

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 (9): 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)

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	3
cytoskeleton	2
developmental process involved in reproduction	1
male gamete generation	1
peptidyl-glutamic acid modification	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
protein metabolic process	1
macromolecule modification	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
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

Protein interactions and networks

STRING

276 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTLL8	LRRC63	Q05C16	529
TTLL8	ANKRD60	Q9BZ19	493
TTLL8	SPATA31A1	Q5TZJ5	480
TTLL8	CCDC74B	Q96LY2	471
TTLL8	C12orf42	Q96LP6	454
TTLL8	SVBP	Q8N300	433
TTLL8	FAM47C	Q5HY64	419
TTLL8	ATAT1	Q5SQI0	413
TTLL8	TTLL4	Q14679	409
TTLL8	TTLL12	Q14166	391
TTLL8	CCDC149	Q6ZUS6	391
TTLL8	ZNF775	Q96BV0	381
TTLL8	SHISA8	B8ZZ34	380
TTLL8	ARMC3	Q5W041	356
TTLL8	SUN3	Q8TAQ9	350

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A1W2PPD8, A2A3K4, A4Q9E5, A4Q9F0, A4Q9F1, A6PVC2, A7E379, B2GUB3, D3YWQ0, F1MAB7, O00295, O15021, O75912, O89084, O94953, O94966, P03177, P15304, P46686, P54748, Q08493, Q0P4M4, Q14999, Q1ECV4, Q1HVD1, Q28969, Q3KSQ2, Q3ULB5, Q4G017, Q5R8Z4, Q5R978, Q5RCJ3, Q5TKR9, Q6EEF3, Q6EMB2, Q6J1Y9, Q6NZK8, Q6X4W1, Q6ZT98, Q7TNN8

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

5561 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000019421 (22:50026317 G>A,T), RS1000162593 (22:50031471 C>T), RS1000200873 (22:50045067 T>C), RS1000230196 (22:50023641 C>T), RS1000275981 (22:50057354 T>A,G), RS1000348934 (22:50056892 T>A,C), RS1000431511 (22:50033751 G>A), RS1000467628 (22:50030293 G>A,T), RS1000486102 (22:50046081 A>C), RS1000630575 (22:50058326 G>T), RS1000670478 (22:50026239 G>A,C), RS1000687569 (22:50058528 C>T), RS1000706593 (22:50023811 G>C), RS1000767736 (22:50035853 C>T), RS1000796890 (22:50018842 A>G)

Disease associations

OMIM: gene MIM:619193 | 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
GCST003472_18	Oppositional defiant disorder dimensions in attention-deficit hyperactivity disorder	7.000000e-06
GCST004133_55	Ulcerative colitis	2.000000e-10
GCST004766_26	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	8.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007679	oppositional defiant disorder measurement
EFO:0007681	triglyceride change measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
benzo(e)pyrene	increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	affects methylation, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Copper	affects cotreatment, decreases expression	1
Methapyrilene	increases methylation	1
Smoke	increases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1
Particulate Matter	increases abundance, affects methylation	1

Clinical trials (associated diseases)

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