TUBA3D

Summary

TUBA3D (tubulin alpha 3d, HGNC:24071) is a protein-coding gene on chromosome 2q21.1, encoding Tubulin alpha-3D chain (P0DPH8). Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers. It is a selective cancer dependency (DepMap: 16.4% of cell lines).

This gene encodes a member of the alpha tubulin family. Tubulin is a major component of microtubules, which are composed of alpha- and beta-tubulin heterodimers and microtubule-associated proteins in the cytoskeleton. Microtubules maintain cellular structure, function in intracellular transport, and play a role in spindle formation during mitosis.

Source: NCBI Gene 113457 — RefSeq curated summary.

At a glance

• Gene–disease (curated): keratoconus 9 (Limited, GenCC)
• Clinical variants (ClinVar): 3 total
• Phenotypes (HPO): 5
• Cancer dependency (DepMap): dependent in 16.4% of screened cell lines
• MANE Select transcript: NM_080386

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24071
Approved symbol	TUBA3D
Name	tubulin alpha 3d
Location	2q21.1
Locus type	gene with protein product
Status	Approved
Aliases	H2-ALPHA
Ensembl gene	ENSG00000075886
Ensembl biotype	protein_coding
OMIM	617878
Entrez	113457

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000321253, ENST00000409047

RefSeq mRNA: 1 — MANE Select: NM_080386 NM_080386

CCDS: CCDS33290

Canonical transcript exons

ENST00000321253 — 5 exons

Exon	Start	End
ENSE00001957482	131476119	131476202
ENSE00002481699	131482552	131482934
ENSE00002489437	131478164	131478386
ENSE00002526860	131480069	131480749
ENSE00003555115	131479308	131479456

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 99.02.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3667 / max 360.8680, expressed in 5 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22549	0.3250	5
202393	0.0418	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	99.02	gold quality
left testis	UBERON:0004533	98.82	gold quality
testis	UBERON:0000473	98.09	gold quality
heart left ventricle	UBERON:0002084	93.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.39	gold quality
apex of heart	UBERON:0002098	88.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.02	gold quality
heart	UBERON:0000948	81.68	gold quality
fallopian tube	UBERON:0003889	76.27	gold quality
right atrium auricular region	UBERON:0006631	75.52	gold quality
left uterine tube	UBERON:0001303	73.74	gold quality
right uterine tube	UBERON:0001302	70.62	gold quality
prostate gland	UBERON:0002367	70.36	gold quality
body of uterus	UBERON:0009853	70.03	gold quality
endocervix	UBERON:0000458	69.31	gold quality
smooth muscle tissue	UBERON:0001135	66.46	gold quality
cerebellar hemisphere	UBERON:0002245	65.82	gold quality
cerebellum	UBERON:0002037	65.76	gold quality
cerebellar cortex	UBERON:0002129	65.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	65.35	gold quality
stromal cell of endometrium	CL:0002255	65.15	gold quality
myometrium	UBERON:0001296	65.05	gold quality
uterine cervix	UBERON:0000002	64.56	gold quality
left ovary	UBERON:0002119	63.70	gold quality
Brodmann (1909) area 9	UBERON:0013540	63.60	gold quality
right ovary	UBERON:0002118	62.84	gold quality
ovary	UBERON:0000992	62.68	gold quality
ectocervix	UBERON:0012249	62.51	gold quality
right lobe of thyroid gland	UBERON:0001119	62.28	gold quality
lymph node	UBERON:0000029	62.16	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1175.93
E-GEOD-124263	yes	808.09
E-ANND-3	yes	11.32

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 1)

• TUBA3D is a new gene that causes keratoconus.The c.31 C > T (Gln11stop) and c.201insTT (Val68Leufs*2) mutations lead to TUBA3D degradation and higher matrix metalloproteinases expression in cornea fibroblasts. (PMID:29051577)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tuba7l	ENSDARG00000104643
rattus_norvegicus	Tuba3a	ENSRNOG00000031707
drosophila_melanogaster	alphaTub84B	FBGN0003884
drosophila_melanogaster	alphaTub84D	FBGN0003885

Paralogs (23): TUBG2 (ENSG00000037042), TUBE1 (ENSG00000074935), TUBB1 (ENSG00000101162), TUBB4A (ENSG00000104833), TUBD1 (ENSG00000108423), TUBA1B (ENSG00000123416), TUBA4A (ENSG00000127824), TUBG1 (ENSG00000131462), TUBB2A (ENSG00000137267), TUBB2B (ENSG00000137285), TUBA3E (ENSG00000152086), TUBA1A (ENSG00000167552), TUBA1C (ENSG00000167553), TUBB8B (ENSG00000173213), TUBB6 (ENSG00000176014), TUBAL3 (ENSG00000178462), TUBA8 (ENSG00000183785), TUBB4B (ENSG00000188229), TUBB (ENSG00000196230), TUBA3C (ENSG00000198033), TUBA4B (ENSG00000243910), TUBB3 (ENSG00000258947), TUBB8 (ENSG00000261456)

Protein

Protein identifiers

Tubulin alpha-3D chain — P0DPH8 (reviewed: P0DPH8)

Alternative names: Alpha-tubulin 3D

All UniProt accessions (2): P0DPH8, Q1ZYQ1

UniProt curated annotations — full annotation on UniProt →

Function. Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers. Microtubules grow by the addition of GTP-tubulin dimers to the microtubule end, where a stabilizing cap forms. Below the cap, tubulin dimers are in GDP-bound state, owing to GTPase activity of alpha-tubulin.

Subunit / interactions. Dimer of alpha and beta chains. A typical microtubule is a hollow water-filled tube with an outer diameter of 25 nm and an inner diameter of 15 nM. Alpha-beta heterodimers associate head-to-tail to form protofilaments running lengthwise along the microtubule wall with the beta-tubulin subunit facing the microtubule plus end conferring a structural polarity. Microtubules usually have 13 protofilaments but different protofilament numbers can be found in some organisms and specialized cells.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in the cornea, sclera, and peripheral blood.

Post-translational modifications. Some glutamate residues at the C-terminus are polyglutamylated, resulting in polyglutamate chains on the gamma-carboxyl group. Polyglutamylation plays a key role in microtubule severing by spastin (SPAST). SPAST preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity by SPAST increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold. Glutamylation is also involved in cilia motility. Some glutamate residues at the C-terminus are monoglycylated but not polyglycylated due to the absence of functional TTLL10 in human. Monoglycylation is mainly limited to tubulin incorporated into cilia and flagella axonemes, which is required for their stability and maintenance. Flagella glycylation controls sperm motility. Both polyglutamylation and monoglycylation can coexist on the same protein on adjacent residues, and lowering glycylation levels increases polyglutamylation, and reciprocally. Acetylation of alpha chains at Lys-40 is located inside the microtubule lumen. This modification has been correlated with increased microtubule stability, intracellular transport and ciliary assembly. Methylation of alpha chains at Lys-40 is found in mitotic microtubules and is required for normal mitosis and cytokinesis contributing to genomic stability. Nitration of Tyr-450 is irreversible and interferes with normal dynein intracellular distribution. Undergoes a tyrosination/detyrosination cycle, the cyclic removal and re-addition of a C-terminal tyrosine residue by the enzymes tubulin tyrosine carboxypeptidase (MATCAP1/KIAA0895L, VASH1 or VASH2) and tubulin tyrosine ligase (TTL), respectively. Tyrosination promotes microtubule interaction with CAP-Gly domain-containing proteins such as CLIP1, CLIP2 and DCTN1. Tyrosination regulates the initiation of dynein-dynactin motility via interaction with DCTN1, which brings the dynein-dynactin complex into contact with microtubules. In neurons, tyrosinated tubulins mediate the initiation of retrograde vesicle transport. Detyrosination is involved in metaphase plate congression by guiding chromosomes during mitosis: detyrosination promotes interaction with CENPE, promoting pole-proximal transport of chromosomes toward the equator. Detyrosination increases microtubules-dependent mechanotransduction in dystrophic cardiac and skeletal muscle. In cardiomyocytes, detyrosinated microtubules are required to resist to contractile compression during contraction: detyrosination promotes association with desmin (DES) at force-generating sarcomeres, leading to buckled microtubules and mechanical resistance to contraction.

Disease relevance. Keratoconus 9 (KTCN9) [MIM:617928] An autosomal dominant form of keratoconus, a common degenerative corneal disease characterized by progressive, non-inflammatory thinning of the corneal stroma, corneal ectasia, and cone-shaped corneal protrusion that results in reduced vision. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MREC motif may be critical for tubulin autoregulation.

Similarity. Belongs to the tubulin family.

RefSeq proteins (1): NP_525125* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000217	Tubulin	Family
IPR002452	Alpha_tubulin	Family
IPR003008	Tubulin_FtsZ_GTPase	Domain
IPR008280	Tub_FtsZ_C	Homologous_superfamily
IPR017975	Tubulin_CS	Conserved_site
IPR018316	Tubulin/FtsZ_2-layer-sand-dom	Domain
IPR023123	Tubulin_C	Homologous_superfamily
IPR036525	Tubulin/FtsZ_GTPase_sf	Homologous_superfamily
IPR037103	Tubulin/FtsZ-like_C	Homologous_superfamily

Pfam: PF00091, PF03953

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (20 total): binding site 9, modified residue 4, chain 2, site 1, sequence variant 1, sequence conflict 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DPH8-F1	91.57	0.82

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): 450 (involved in polymerization); 254

Ligand- & substrate-binding residues (9): 179; 206; 228; 11; 71; 71; 140; 144; 145

Post-translational modifications (4): 40, 282, 439, 450

Function

Pathways and Gene Ontology

Reactome pathways

86 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-190840	Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
R-HSA-190861	Gap junction assembly
R-HSA-2132295	MHC class II antigen presentation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-3371497	HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand
R-HSA-380320	Recruitment of NuMA to mitotic centrosomes
R-HSA-389957	Prefoldin mediated transfer of substrate to CCT/TriC
R-HSA-389960	Formation of tubulin folding intermediates by CCT/TriC
R-HSA-389977	Post-chaperonin tubulin folding pathway
R-HSA-437239	Recycling pathway of L1
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-5620920	Cargo trafficking to the periciliary membrane
R-HSA-5620924	Intraflagellar transport
R-HSA-5626467	RHO GTPases activate IQGAPs
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-6807878	COPI-mediated anterograde transport
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-6811436	COPI-independent Golgi-to-ER retrograde traffic
R-HSA-68877	Mitotic Prometaphase
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint
R-HSA-8955332	Carboxyterminal post-translational modifications of tubulin
R-HSA-9609690	HCMV Early Events
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9619483	Activation of AMPK downstream of NMDARs
R-HSA-9646399	Aggrephagy
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-9668328	Sealing of the nuclear envelope (NE) by ESCRT-III
R-HSA-983189	Kinesins

MSigDB gene sets: 163 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_MEMBRANE_TRAFFICKING, PATIL_LIVER_CANCER, UEDA_PERIFERAL_CLOCK, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM6, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_DN, GOBP_MITOTIC_CELL_CYCLE, REACTOME_GAP_JUNCTION_ASSEMBLY, REACTOME_TRANSMISSION_ACROSS_CHEMICAL_SYNAPSES, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, GOCC_CILIUM, TOMIDA_METASTASIS_UP, GOMF_STRUCTURAL_CONSTITUENT_OF_CYTOSKELETON

GO Biological Process (4): microtubule cytoskeleton organization (GO:0000226), mitotic cell cycle (GO:0000278), cytoskeleton organization (GO:0007010), microtubule-based process (GO:0007017)

GO Molecular Function (5): structural constituent of cytoskeleton (GO:0005200), GTP binding (GO:0005525), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), nucleotide binding (GO:0000166)

GO Cellular Component (5): cytoplasm (GO:0005737), microtubule (GO:0005874), cilium (GO:0005929), microtubule cytoskeleton (GO:0015630), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Mitotic Prometaphase	2
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	2
Assembly of the 9+0 primary cilium	2
RHO GTPase Effectors	2
Golgi-to-ER retrograde transport	2
Membrane Trafficking	1
Transport of connexons to the plasma membrane	1
Gap junction trafficking	1
Adaptive Immune System	1
Mitotic Anaphase	1
Cellular responses to stress	1
Protein folding	1
L1CAM interactions	1
Signaling by Hedgehog	1
ER to Golgi Anterograde Transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoskeleton organization	2
cytoskeleton	2
microtubule-based process	1
cell cycle	1
mitotic nuclear division	1
organelle organization	1
cellular process	1
structural molecule activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
catalytic activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A5A6J1, P02550, P02552, P05213, P05214, P06603, P06604, P06605, P08537, P09644, P0DPH7, P0DPH8, P18258, P18288, P30436, P34690, P36220, P41383, P52273, P68360, P68361, P68362, P68363, P68365, P68366, P68367, P68368, P68369, P68370, P68373, P81947, P81948, Q06331, Q28IX8, Q2HJ86, Q2XVP4, Q32KN8, Q3ZCJ7, Q4R538, Q52PV9

Diamond homologs: A0AAL4, A5A6J1, B9DGT7, B9DHQ0, O22347, O22348, O22349, P02550, P02552, P04105, P04106, P05213, P05214, P06603, P06604, P08537, P09204, P09205, P09243, P0DPH7, P0DPH8, P10872, P10873, P11139, P11237, P11480, P11481, P12543, P14640, P14641, P14642, P18258, P18288, P22275, P28268, P28287, P28752, P29511, P30436, P32255

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“Elongator complex”	“up-regulates activity”	TUBA3D	acetylation
TUBA3D	up-regulates	Neuron_migration
ATAT1	“up-regulates quantity by stabilization”	TUBA3D	acetylation

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	1
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

816 predictions. Top by Δscore:

Variant	Effect	Δscore
2:131478155:T:TA	acceptor_gain	1.0000
2:131478160:A:AG	acceptor_gain	1.0000
2:131478161:C:G	acceptor_gain	1.0000
2:131478162:A:AG	acceptor_gain	1.0000
2:131478162:A:C	acceptor_loss	1.0000
2:131478162:AGC:A	acceptor_gain	1.0000
2:131478162:AGCGC:A	acceptor_gain	1.0000
2:131478163:G:GA	acceptor_gain	1.0000
2:131478163:GC:G	acceptor_gain	1.0000
2:131478163:GCG:G	acceptor_gain	1.0000
2:131478163:GCGC:G	acceptor_gain	1.0000
2:131478163:GCGCG:G	acceptor_gain	1.0000
2:131478337:C:T	donor_gain	1.0000
2:131478383:GTCG:G	donor_gain	1.0000
2:131478386:GGTA:G	donor_loss	1.0000
2:131478387:G:GG	donor_gain	1.0000
2:131478387:GTAG:G	donor_loss	1.0000
2:131478388:T:G	donor_loss	1.0000
2:131479303:T:A	acceptor_gain	1.0000
2:131479306:A:AG	acceptor_gain	1.0000
2:131479306:A:G	acceptor_loss	1.0000
2:131479306:AGAT:A	acceptor_gain	1.0000
2:131479307:G:GT	acceptor_gain	1.0000
2:131479307:GA:G	acceptor_gain	1.0000
2:131479307:GAT:G	acceptor_gain	1.0000
2:131479307:GATG:G	acceptor_gain	1.0000
2:131479307:GATGA:G	acceptor_gain	1.0000
2:131479452:AACTG:A	donor_gain	1.0000
2:131479453:ACTG:A	donor_gain	1.0000
2:131479454:CTG:C	donor_gain	1.0000

AlphaMissense

2955 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1001305595 (2:131477504 C>G), RS1002819666 (2:131477999 T>C), RS1002902032 (2:131475038 G>A), RS1002974080 (2:131474709 C>A,G), RS1003667640 (2:131479714 C>A,T), RS1003773994 (2:131479033 T>C), RS1004723294 (2:131479906 G>A,C), RS1004823708 (2:131475343 T>G), RS1005397689 (2:131483102 T>C), RS1005421286 (2:131476278 T>C), RS1005677070 (2:131476533 A>G), RS1005843301 (2:131481284 T>A), RS1007068686 (2:131483206 T>C), RS1007186242 (2:131477220 T>C), RS1007214433 (2:131482415 G>A)

Disease associations

OMIM: gene MIM:617878 | disease phenotypes: MIM:617928

GenCC curated gene-disease

Disease	Classification	Inheritance
keratoconus 9	Limited	Unknown

Mondo (1): keratoconus 9 (MONDO:0054771)

Orphanet (0):

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000563	Keratoconus
HP:0003621	Juvenile onset
HP:0007663	Reduced visual acuity
HP:0100689	Decreased corneal thickness

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

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects binding, increases expression, affects expression, increases reaction	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
sulforaphane	affects binding	1
cupric chloride	decreases expression	1
cupric oxide	decreases expression	1
phenethyl isothiocyanate	affects binding	1
CGP 52608	affects binding, increases reaction	1
bromovanin	increases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	decreases expression	1
Atrazine	increases expression	1
Calcitriol	increases expression, affects cotreatment	1
Cocaine	decreases expression	1
Demecolcine	decreases expression	1
Hydrogen Peroxide	affects expression	1
Dihydrotestosterone	increases expression	1
Testosterone	affects cotreatment, increases expression	1
Vincristine	decreases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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