TPPP

Summary

TPPP (tubulin polymerization promoting protein, HGNC:24164) is a protein-coding gene on chromosome 5p15.33, encoding Tubulin polymerization-promoting protein (O94811). Regulator of microtubule dynamics that plays a key role in myelination by promoting elongation of the myelin sheath.

Enables several functions, including magnesium ion binding activity; microtubule nucleator activity; and protein homodimerization activity. Involved in several processes, including microtubule cytoskeleton organization; negative regulation of tubulin deacetylation; and positive regulation of protein polymerization. Located in several cellular components, including cytoskeleton; mitochondrion; and perinuclear region of cytoplasm. Is active in Golgi apparatus.

Source: NCBI Gene 11076 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 23 total
• MANE Select transcript: NM_007030

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24164
Approved symbol	TPPP
Name	tubulin polymerization promoting protein
Location	5p15.33
Locus type	gene with protein product
Status	Approved
Aliases	p25alpha, TPPP1, p25, TPPP/p25
Ensembl gene	ENSG00000171368
Ensembl biotype	protein_coding
OMIM	608773
Entrez	11076

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000360578, ENST00000889051, ENST00000889052, ENST00000889053, ENST00000889054, ENST00000889055, ENST00000889056, ENST00000889057, ENST00000889058, ENST00000889059, ENST00000941396, ENST00000941397, ENST00000941398, ENST00000941399

RefSeq mRNA: 1 — MANE Select: NM_007030 NM_007030

CCDS: CCDS3856

Canonical transcript exons

ENST00000360578 — 4 exons

Exon	Start	End
ENSE00001134653	665970	666123
ENSE00001323781	677750	678064
ENSE00001360334	693278	693352
ENSE00001419344	659862	665296

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 99.74.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4308 / max 574.4817, expressed in 464 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60724	6.3068	452
60725	0.1240	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.74	gold quality
middle temporal gyrus	UBERON:0002771	99.73	gold quality
postcentral gyrus	UBERON:0002581	99.50	gold quality
parietal lobe	UBERON:0001872	99.45	gold quality
medial globus pallidus	UBERON:0002477	99.40	gold quality
entorhinal cortex	UBERON:0002728	99.37	gold quality
globus pallidus	UBERON:0001875	99.23	gold quality
inferior vagus X ganglion	UBERON:0005363	99.14	gold quality
superior frontal gyrus	UBERON:0002661	99.03	gold quality
ventral tegmental area	UBERON:0002691	98.89	gold quality
superior vestibular nucleus	UBERON:0007227	98.84	gold quality
subthalamic nucleus	UBERON:0001906	98.65	gold quality
occipital lobe	UBERON:0002021	98.64	gold quality
primary visual cortex	UBERON:0002436	98.64	gold quality
endothelial cell	CL:0000115	98.43	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.31	gold quality
pons	UBERON:0000988	98.20	gold quality
lateral globus pallidus	UBERON:0002476	98.16	gold quality
temporal lobe	UBERON:0001871	98.02	gold quality
right frontal lobe	UBERON:0002810	98.01	gold quality
prefrontal cortex	UBERON:0000451	97.98	gold quality
substantia nigra pars compacta	UBERON:0001965	97.92	gold quality
Ammon’s horn	UBERON:0001954	97.90	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.50	gold quality
frontal cortex	UBERON:0001870	97.29	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.27	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.21	gold quality
amygdala	UBERON:0001876	97.12	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.12	gold quality
medulla oblongata	UBERON:0001896	96.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	11.13
E-ANND-3	yes	3.58

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

213 targeting TPPP, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 40)

• TPPP/p25 has a role in stabilization of physiological microtubular ultrastructures and cell survival (PMID:15564385)
• perhaps p25alpha plays a pro-aggregatory role in the common neurodegenerative disorders hall-marked by alpha-synuclein aggregates (PMID:15590652)
• Recombinant TPPP plays an important role for tubulin-related transport in developing, myelinating oligodendrocytes. (PMID:16879710)
• identified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a new interacting partner of TPPP/p25 within the alpha-synuclein positive Lewy body (PMID:17027006)
• ERK2 can regulate TPPP activity via the phosphorylation of Thr(14) and/or Ser(18) in its unfolded N-terminal tail (PMID:17693641)
• Myelin basic protein and p25alpha colocalize in myelin in normal human brains. (PMID:17823288)
• data suggest that gain of 5p15.33 (TPPP and ZDHHC11) may become a potential biomarker identifying high-risk patients with disease progression in bladder cancer. (PMID:18025801)
• LIMK1 phosphorylation of p25 blocks p25 activity, thus promoting microtubule disassembly. (PMID:18028908)
• we review evidence pertaining to the role of GSK3 in the myocardium and discuss effects of genetic manipulation of GSK3 activity in vivo–REVIEW (PMID:18204489)
• GSK-3 is involved in the regulation of, and cross-talk between, two major forms of synaptic plasticity, N-methyl-D-aspartate receptor dependent long-term potentiation and NMDAR-dependent long-term depression–REVIEW (PMID:18311157)
• contribution of GSK3 in growth regulation of myeloma cells (PMID:18728964)
• Data suggest that the intracellular level of TPPP/p25 influences the cell differentiation, proliferation and the formation of protein aggregates, and consequently, the etiology of central nervous system diseases. (PMID:19382230)
• The RING domain of XIAP (and probably cIAP-1 and cIAP-2) associates with GSK3, GSK3 acts upstream of the apoptosome to promote intrinsic apoptosis, and the association between XIAP and GSK3 may block the pro-apoptotic function of GSK3. (PMID:19698783)
• TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6 (PMID:20308065)
• Although serine-129 phosphorylation of alpha-synuclein facilitates TPPP-mediated alpha-SYN oligomerization, this modification does not seem to play an inevitable role in the early step of alpha-SYN oligomer formation in a cellular model of multiple system atrophy. (PMID:20849899)
• these investigations suggest the CSF-TPPP/p25 level could become diagnostic marker of MS and other demyelination-related diseases. (PMID:21565174)
• This study demonistrated that p25 is generated during spatial memory formation. (PMID:21616478)
• Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. (PMID:21832049)
• Data show that TPPP may work as a protective factor for cells against the damage effects of the accumulation of abnormal forms of PrPs, besides its function as an agent for dynamic stabilization of microtubular ultrastructures. (PMID:21857997)
• GSK3 has a significant role in maintaining repression of growth factor-inducible genes during quiescence. CREB, NFkB and AP-1 mediate this regulation of gene expression by GSK-3. (PMID:21900749)
• Binding of Zn(2) bivalent cation to structurally disordered TPPP/p25 influences TPPP/p25-promoted tubulin polymerization and GTPase activity. (PMID:21995432)
• Wnt induces the phosphorylation of LRP6 which consequently access the catalytic pocket of GSK3 as pseudo-substrates, thus directly blocking its activity against beta-catenin. (PMID:22083140)
• The authors conclude that the modest structural changes that p25alpha undergoes can promote weak intermolecular contacts and that polyanions such as heparin play a central role in stabilizing these aggregates. (PMID:22326478)
• The RhoA-ROCK-LIMK2-TPPP pathway controls metaphase spindle-orientation; TPPP colocalizes with LIMK2 at the mitotic spindle. (PMID:22328514)
• GSK3 promotes the mitochondrial translocation of p53, enabling its interaction with Bcl2 to allow Bax oligomerization and the subsequent release of cytochrome C. (PMID:23161404)
• dual Rock and Cdk phosphorylation of Tppp1 inhibits its regulation of the cell cycle to increase cell proliferation (PMID:23355470)
• results suggest that ROCK regulates beta-catenin stability in cells via preventing TPPP1-mediated inhibition of HDAC6 activity, to reduce its acetylation and degradation via phosphorylation by CK1 and GSK3beta (PMID:23727580)
• Epigenetic changes in TPPP, in combination with experiences of maltreatment, may confer risk for depression in children. (PMID:24655651)
• suggest that the zinc as a specific divalent cation could be involved in the fine-tuning of the physiological TPPP/p25 level counteracting both the enrichment and the lack of this protein leading to distinct central nervous system diseases (PMID:25445539)
• the central folded domain of TPPP/p25 following binding to microtubules can drive s homotypic protein-protein interactions leading to bundled microtubules. (PMID:26289831)
• Results reveal a link between p25 and BACE1 in Alzheimer disease (AD) brains and suggest that upregulated Cdk5 activation by p25 accelerates AD pathogenesis by enhancing BACE1 activity via phosphorylation. (PMID:26317805)
• This study demonstrated that the AAV9-mediated p25 overexpression mouse model, which is a practical model exhibiting neurodegeneration-like pathological and behavioral changes. (PMID:27258419)
• TPPP may have a role in poor prognosis in hepatocellular carcinoma (PMID:27630306)
• TPPP/p25 is co-enriched and co-localized with alpha-synuclein in brain inclusions of Parkinson’s disease patients. Interaction of alpha-synuclein with various deletion mutants and fragments of TPPP/p25 were characterized. (PMID:27671864)
• The objective of this paper is to highlight a critical point of a recently published Skoufias’s paper in which the crucial role of the microtubules in TPPP/p25 dimerization leading to microtubule bundling was suggested. (PMID:28074911)
• The knowledge accumulated so far underlines the key roles of the multifunctional TPPP/p25 in both physiological and diverse pathological processes, consequently its validation as drug target sorely needs a new innovative strategy that is briefly reviewed here. (PMID:28271739)
• The binding of TPPP/p25 to a new binding site of DYNLL/LC8, outside the canonical binding groove, counteracted the TPPP/p25-derived hyperacetylation of the microtubule network. (PMID:31505170)
• These results demonstrate that TPPP on Golgi outposts are important for local microtubule nucleation and myelin sheath elongation. (PMID:31522887)
• This study revealed the low expression level of TPPP in pancreatic cancer cells. In addition, the high expression of TPPP promotes the invasion, migration and angiogenesis of pancreatic cancer cells. (PMID:31631174)
• Anti-Aggregative Effect of the Antioxidant DJ-1 on the TPPP/p25-Derived Pathological Associations of Alpha-Synuclein. (PMID:34831132)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	TPPP	ENSDARG00000105029
mus_musculus	Tppp	ENSMUSG00000021573
rattus_norvegicus	Tppp	ENSRNOG00000028261
drosophila_melanogaster	ringer	FBGN0266417
caenorhabditis_elegans	tppp-1	WBGENE00016321

Paralogs (2): TPPP3 (ENSG00000159713), TPPP2 (ENSG00000179636)

Protein

Protein identifiers

Tubulin polymerization-promoting protein — O94811 (reviewed: O94811)

Alternative names: 25 kDa brain-specific protein, TPPP/p25, p24, p25-alpha

All UniProt accessions (2): O94811, Q4L233

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of microtubule dynamics that plays a key role in myelination by promoting elongation of the myelin sheath. Acts as a microtubule nucleation factor in oligodendrocytes: specifically localizes to the postsynaptic Golgi apparatus region, also named Golgi outpost, and promotes microtubule nucleation, an important step for elongation of the myelin sheath. Required for both uniform polarized growth of distal microtubules as well as directing the branching of proximal processes. Shows magnesium-dependent GTPase activity; the role of the GTPase activity is unclear. In addition to microtubule nucleation activity, also involved in microtubule bundling and stabilization of existing microtubules, thereby maintaining the integrity of the microtubule network. Regulates microtubule dynamics by promoting tubulin acetylation: acts by inhibiting the tubulin deacetylase activity of HDAC6. Also regulates cell migration: phosphorylation by ROCK1 inhibits interaction with HDAC6, resulting in decreased acetylation of tubulin and increased cell motility. Plays a role in cell proliferation by regulating the G1/S-phase transition. Involved in astral microtubule organization and mitotic spindle orientation during early stage of mitosis; this process is regulated by phosphorylation by LIMK2.

Subunit / interactions. Homodimer. Binds tubulin; binding is inhibited by GTP. Interacts with MAPK1. Interacts with GAPDH; the interaction is direct. Interacts with LIMK1 (via the PDZ domain); the interaction is direct. Interacts with LIMK2. Interacts with HDAC6; thereby inhibiting the tubulin deacetylase activity of HDAC6. Interacts with aggregated SNCA; may have a pro-aggregatory role in synucleinopathies. Interacts with DYNLL1. Interacts (via C-terminus) with S100A2, S100A6 and S100B; these interactions inhibit TPPP dimerization.

Subcellular location. Golgi outpost. Cytoplasm. Cytoskeleton. Microtubule organizing center. Nucleus. Spindle.

Tissue specificity. Widely expressed.

Post-translational modifications. Phosphorylated by LIMK1 on serine residues; phosphorylation may alter the tubulin polymerization activity. Phosphorylation by LIMK2, but not LIMK1, regulates astral microtubule organization at early stage of mitosis. Phosphorylation by ROCK1 at Ser-32, Ser-107 and Ser-159 inhibits interaction with HDAC6, resulting in decreased acetylation of tubulin, increased cell motility and entry into S-phase. Phosphorylation by CDK1 inhibits the microtubule polymerizing activity. Degraded by the proteasome; zinc-binding inhibits degradation by the proteasome.

Domain organisation. Most of the protein is composed of disordered regions. Zinc-binding induces structural rearrangement by promoting molten globule state formation.

Induction. enriched in cerebrospinal fluid of multiple sclerosis patients (at protein level).

Similarity. Belongs to the TPPP family.

RefSeq proteins (1): NP_008961* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008907	TPP/p25	Family
IPR011992	EF-hand-dom_pair	Homologous_superfamily

Pfam: PF05517

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (34 total): mutagenesis site 14, modified residue 9, binding site 4, region of interest 3, compositionally biased region 2, chain 1, glycosylation site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
9J4F	ELECTRON MICROSCOPY	2.49
9J4D	ELECTRON MICROSCOPY	2.93
9J4E	ELECTRON MICROSCOPY	3.32

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O94811-F1	79.16	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (4): 61; 72; 80; 83

Post-translational modifications (9): 14, 18, 32, 35, 45, 92, 107, 159, 160

Glycosylation sites (1): 152

Mutagenesis-validated functional residues (14):

Position	Phenotype
14	in 4ala; abolished phosphorylation by cdk1 without affecting g1/s-phase transition; when associated with a-18, a-45 and
14	in 4glu; phosphomimetic mutant, does not affect g1/s-phase transition; when associated with e-18, e-45 and e-160.
18	in 4ala; abolished phosphorylation by cdk1 without affecting g1/s-phase transition; when associated with a-14, a-45 and
18	in 4glu; phosphomimetic mutant, does not affect g1/s-phase transition; when associated with e-14, e-45 and e-160.
32	in 3ala; abolished phosphorylation by rock1, leading to delayed entry into s-phase; when associated with a-107 and a-159
32	in 3glu; phosphomimetic mutant, leading to decreased transition of the g1/s-phase; when associated with e-07 and e-159.
45	in 4ala; abolished phosphorylation by cdk1 without affecting g1/s-phase transition; when associated with a-14, a-18 and
45	in 4glu; phosphomimetic mutant, does not affect g1/s-phase transition; when associated with e-14, e-18 and e-160.
107	in 3ala; abolished phosphorylation by rock1, leading to delayed entry into s-phase; when associated with a-32 and a-159.
107	in 3glu; phosphomimetic mutant, leading to decreased transition of the g1/s-phase; when associated with e-32 and e-159.
159	in 3ala; abolished phosphorylation by rock1, leading to delayed entry into s-phase; when associated with a-32 and a-107.
159	in 3glu; phosphomimetic mutant, leading to decreased transition of the g1/s-phase; when associated with e-32 and e-107.
160	in 4ala; abolished phosphorylation by cdk1 without affecting g1/s-phase transition; when associated with a-14, a-18 and
160	in 4glu; phosphomimetic mutant, does not affect g1/s-phase transition; when associated with e-14, e-18 and e-45.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 188 (showing top): GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_REGULATION_OF_PROTEIN_DEACETYLATION, GOBP_MACROMOLECULE_DEACYLATION, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_MYELINATION, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT, GOBP_MICROTUBULE_NUCLEATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN

GO Biological Process (13): microtubule bundle formation (GO:0001578), oligodendrocyte development (GO:0014003), astral microtubule organization (GO:0030953), positive regulation of protein-containing complex assembly (GO:0031334), positive regulation of myelination (GO:0031643), positive regulation of protein polymerization (GO:0032273), myelin assembly (GO:0032288), microtubule polymerization (GO:0046785), oligodendrocyte differentiation (GO:0048709), cell division (GO:0051301), microtubule nucleation by microtubule organizing center (GO:0051418), regulation of microtubule cytoskeleton organization (GO:0070507), negative regulation of tubulin deacetylation (GO:1904428)

GO Molecular Function (8): magnesium ion binding (GO:0000287), GTPase activity (GO:0003924), microtubule binding (GO:0008017), tubulin binding (GO:0015631), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), microtubule organizing center (GO:0005815), cytosol (GO:0005829), microtubule (GO:0005874), perinuclear region of cytoplasm (GO:0048471), mitotic spindle (GO:0072686), postsynaptic Golgi apparatus (GO:0150051), Golgi apparatus (GO:0005794), spindle (GO:0005819), cytoskeleton (GO:0005856), microtubule bundle (GO:0097427)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
intracellular membrane-bounded organelle	3
microtubule cytoskeleton	3
microtubule cytoskeleton organization	2
myelination	2
protein polymerization	2
microtubule nucleation	2
intracellular membraneless organelle	2
glial cell development	1
oligodendrocyte differentiation	1
spindle organization	1
cytoplasmic microtubule organization	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
regulation of myelination	1
positive regulation of nervous system process	1
positive regulation of cellular process	1
positive regulation of protein-containing complex assembly	1
regulation of protein polymerization	1
cellular component assembly involved in morphogenesis	1
microtubule polymerization or depolymerization	1
supramolecular fiber organization	1
central nervous system development	1
glial cell differentiation	1
cellular process	1
regulation of microtubule-based process	1
regulation of cytoskeleton organization	1
negative regulation of protein modification process	1
tubulin deacetylation	1
regulation of tubulin deacetylation	1
metal ion binding	1
ribonucleoside triphosphate phosphatase activity	1
tubulin binding	1
cytoskeletal protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1

Protein interactions and networks

STRING

1398 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPPP	DCTN2	Q13561	968
TPPP	DCTN1	Q14203	958
TPPP	CAPZA2	P47755	896
TPPP	CAPZA1	P52907	893
TPPP	ACTR10	Q9NZ32	857
TPPP	ACTR3C	Q9C0K3	847
TPPP	ACTR3B	Q9P1U1	844
TPPP	DCTN4	Q9UJW0	806
TPPP	DCTN6	O00399	768
TPPP	SNCA	P37840	738
TPPP	F12	P00748	711
TPPP	FOXQ1	Q9C009	649
TPPP	FOXF2	Q12947	647
TPPP	HDAC6	Q9UBN7	638
TPPP	IL5RA	Q01344	549

IntAct

45 interactions, top by confidence:

A	B	Type	Score
TPPP	SNCA	psi-mi:“MI:0407”(direct interaction)	0.720
TPPP	SNCA	psi-mi:“MI:0915”(physical association)	0.720
SNCA	TPPP	psi-mi:“MI:0915”(physical association)	0.720
SNCA	TPPP	psi-mi:“MI:0403”(colocalization)	0.720
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
LIN28A	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
CDRT15P3	NFKBIE	psi-mi:“MI:0914”(association)	0.620
TPPP	H1-1	psi-mi:“MI:0915”(physical association)	0.560
ZNF114	TPPP	psi-mi:“MI:0915”(physical association)	0.560
TPPP	ZNF114	psi-mi:“MI:0915”(physical association)	0.560
VDAC2	TPPP	psi-mi:“MI:0915”(physical association)	0.560
MAGEB6	TPPP	psi-mi:“MI:0915”(physical association)	0.560
FADD	THAP12	psi-mi:“MI:0914”(association)	0.530
TPPP	TPPP	psi-mi:“MI:0407”(direct interaction)	0.440
	TPPP	psi-mi:“MI:0407”(direct interaction)	0.440
TPPP	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
TPPP	H1-5	psi-mi:“MI:0915”(physical association)	0.400
TPPP	H1-4	psi-mi:“MI:0915”(physical association)	0.400
TPPP	DDB2	psi-mi:“MI:0915”(physical association)	0.400
CDK11B	TPPP	psi-mi:“MI:0915”(physical association)	0.370
APP	ESYT2	psi-mi:“MI:0914”(association)	0.350
GRPEL1	TPPP	psi-mi:“MI:0914”(association)	0.350

BioGRID (48): TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-MS), TPPP (Affinity Capture-RNA), TUBB (Reconstituted Complex), SNCA (Reconstituted Complex), TPPP (Biochemical Activity), ZNF114 (Two-hybrid), HIST1H1A (Proximity Label-MS), DDB2 (Proximity Label-MS), HMGN2 (Proximity Label-MS)

ESM2 similar proteins: A4IIY2, A6ZPY2, D3ZQL7, O18282, O42929, O94811, P0CR50, P0CR51, P18432, P20232, P35600, P36621, P40122, P40124, P47089, P49373, P52652, P55010, P55871, P59282, P59325, P91127, Q01518, Q07205, Q08163, Q08873, Q0P5Y3, Q27957, Q2VPM9, Q3SYV4, Q3T077, Q3ZCC8, Q4QQU6, Q4R3A0, Q4R4I6, Q54LA1, Q5PPN5, Q5R4L0, Q5R8B4, Q6CJ30

Diamond homologs: A4IIY2, B6KAS6, D3ZQL7, O94811, P59282, P91127, Q0P5Y3, Q27957, Q2VPM9, Q3T077, Q3ZCC8, Q4R3A0, Q5PPN5, Q7TQD2, Q9BW30, Q9CRB6, Q9VV43

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
MAPK1	“down-regulates activity”	TPPP	phosphorylation
PRKACA	unknown	TPPP	phosphorylation
CDK5	“down-regulates activity”	TPPP	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1645 predictions. Top by Δscore:

Variant	Effect	Δscore
5:665131:AGGTG:A	donor_gain	1.0000
5:665161:AG:A	donor_gain	1.0000
5:665293:CTTT:C	acceptor_gain	1.0000
5:665294:TTT:T	acceptor_gain	1.0000
5:665295:TT:T	acceptor_gain	1.0000
5:665295:TTC:T	acceptor_loss	1.0000
5:665296:TCT:T	acceptor_loss	1.0000
5:665297:C:CC	acceptor_gain	1.0000
5:665964:GCTCA:G	donor_loss	1.0000
5:665965:CTCAC:C	donor_loss	1.0000
5:665966:TCAC:T	donor_loss	1.0000
5:665967:CACC:C	donor_loss	1.0000
5:665969:C:A	donor_loss	1.0000
5:666120:CCCT:C	acceptor_gain	1.0000
5:666121:CCTC:C	acceptor_gain	1.0000
5:666124:C:CC	acceptor_gain	1.0000
5:677743:CACT:C	donor_loss	1.0000
5:677745:CTCA:C	donor_gain	1.0000
5:677746:TCA:T	donor_loss	1.0000
5:677747:CA:C	donor_loss	1.0000
5:677748:A:AC	donor_gain	1.0000
5:677748:A:C	donor_loss	1.0000
5:677749:C:CA	donor_gain	1.0000
5:677749:CTTG:C	donor_gain	1.0000
5:678060:TGTTG:T	acceptor_gain	1.0000
5:678065:C:CC	acceptor_gain	1.0000
5:693273:CTTA:C	donor_loss	1.0000
5:693274:TTACC:T	donor_loss	1.0000
5:693275:TA:T	donor_loss	1.0000
5:693276:A:C	donor_loss	1.0000

AlphaMissense

1424 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:665222:G:C	F180L	1.000
5:665222:G:T	F180L	1.000
5:665224:A:G	F180L	1.000
5:677835:A:G	W76R	1.000
5:677835:A:T	W76R	1.000
5:665223:A:G	F180S	0.999
5:665227:G:T	R179S	0.999
5:665236:G:C	H176D	0.999
5:665241:C:T	G174D	0.999
5:665246:G:C	F172L	0.999
5:665246:G:T	F172L	0.999
5:665247:A:G	F172S	0.999
5:665248:A:G	F172L	0.999
5:665265:A:G	L166P	0.999
5:677761:G:C	F100L	0.999
5:677761:G:T	F100L	0.999
5:677762:A:G	F100S	0.999
5:677763:A:G	F100L	0.999
5:677772:C:G	D97H	0.999
5:677823:A:G	C80R	0.999
5:677825:A:G	L79P	0.999
5:677827:C:A	K78N	0.999
5:677827:C:G	K78N	0.999
5:677829:T:C	K78E	0.999
5:677876:C:T	G62E	0.999
5:677885:G:T	A59D	0.999
5:677887:A:C	F58L	0.999
5:677887:A:T	F58L	0.999
5:677889:A:G	F58L	0.999
5:677896:G:C	F55L	0.999

dbSNP variants (sampled 300 via entrez): RS1000266295 (5:670083 C>T), RS1000291962 (5:691056 CCGGCG>C), RS1000296510 (5:681793 G>C), RS1000304893 (5:677060 C>A,T), RS1000382831 (5:677125 G>A), RS1000389647 (5:681971 G>A), RS1000462308 (5:673175 G>A), RS1000688480 (5:687916 G>A), RS1000704061 (5:672835 G>C), RS1000855216 (5:669492 CTCTG>C), RS1000865928 (5:674102 C>T), RS1000903104 (5:667801 T>C), RS1000977848 (5:663033 T>C), RS1001010204 (5:701944 T>A,G), RS1001088575 (5:667665 T>G)

Disease associations

OMIM: gene MIM:608773 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000624_20	Ulcerative colitis	1.000000e-09
GCST003739_4	Esophageal adenocarcinoma	2.000000e-08
GCST003740_9	Barrett’s esophagus or Esophageal adenocarcinoma	3.000000e-09
GCST004133_71	Ulcerative colitis	2.000000e-07
GCST008058_240	Estimated glomerular filtration rate	1.000000e-13
GCST008061_2	Estimated glomerular filtration rate	1.000000e-06
GCST008745_49	Estimated glomerular filtration rate in non-diabetics	1.000000e-11
GCST008746_4	Estimated glomerular filtration rate in diabetes	3.000000e-11
GCST010172_9	Idiopathic downbeat nystagmus	9.000000e-06
GCST90014033_36	Haemorrhoidal disease	2.000000e-13

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PubChem BioAssay actives

6 with measured affinity, of 6 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]boronic acid	1799504: Cell Proliferation Assay from Article 10.1016/j.chembiol.2005.06.016: “Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.”	ic50	0.0170	uM
2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenol	1799504: Cell Proliferation Assay from Article 10.1016/j.chembiol.2005.06.016: “Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.”	ic50	0.0320	uM

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
Cadmium Chloride	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
bisphenol A	decreases expression, increases methylation	1
trichostatin A	affects expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
(+)-JQ1 compound	increases expression	1
Irinotecan	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects binding, increases expression	1
Lead	affects expression	1
Niclosamide	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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