FKBP8

Summary

FKBP8 (FKBP prolyl isomerase 8, HGNC:3724) is a protein-coding gene on chromosome 19p13.11, encoding Peptidyl-prolyl cis-trans isomerase FKBP8 (Q14318). Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium.

The protein encoded by this gene is a member of the immunophilin protein family, which play a role in immunoregulation and basic cellular processes involving protein folding and trafficking. Unlike the other members of the family, this encoded protein does not seem to have PPIase/rotamase activity. It may have a role in neurons associated with memory function.

Source: NCBI Gene 23770 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spina bifida (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 61 total
• Druggable target: yes
• MANE Select transcript: NM_012181

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3724
Approved symbol	FKBP8
Name	FKBP prolyl isomerase 8
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	FKBP38, FKBPr38
Ensembl gene	ENSG00000105701
Ensembl biotype	protein_coding
OMIM	604840
Entrez	23770

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 50 protein_coding, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000222308, ENST00000544835, ENST00000594844, ENST00000596015, ENST00000596494, ENST00000596558, ENST00000597547, ENST00000597611, ENST00000597960, ENST00000599540, ENST00000601844, ENST00000606531, ENST00000608443, ENST00000609656, ENST00000902303, ENST00000902304, ENST00000902305, ENST00000902306, ENST00000902307, ENST00000902308, ENST00000902309, ENST00000902310, ENST00000902311, ENST00000902312, ENST00000902313, ENST00000902314, ENST00000902315, ENST00000902316, ENST00000923877, ENST00000923878, ENST00000923879, ENST00000923880, ENST00000923881, ENST00000923882, ENST00000923883, ENST00000923884, ENST00000923885, ENST00000923886, ENST00000923887, ENST00000923888, ENST00000959007, ENST00000959008, ENST00000959009, ENST00000959010, ENST00000959011, ENST00000959012, ENST00000959013, ENST00000959014, ENST00000959015, ENST00000959016, ENST00000959017, ENST00000959018

RefSeq mRNA: 2 — MANE Select: NM_012181 NM_001308373, NM_012181

CCDS: CCDS32961, CCDS77266

Canonical transcript exons

ENST00000608443 — 9 exons

Exon	Start	End
ENSE00000691184	18539551	18539720
ENSE00001419038	18543486	18543573
ENSE00003461034	18533270	18533347
ENSE00003542457	18539371	18539459
ENSE00003644477	18541679	18541995
ENSE00003694909	18537601	18537773
ENSE00003698352	18532664	18532795
ENSE00003785364	18538216	18538436
ENSE00003843103	18531763	18532255

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 132.7910 / max 4995.0615, expressed in 1828 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
180031	119.7920	1828
180029	2.9199	850
180030	2.6621	1310
180032	2.0227	822
180022	1.2081	797
180023	1.1835	581
180026	1.0579	596
180027	0.8126	524
180024	0.7745	449
180025	0.2478	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.62	gold quality
right testis	UBERON:0004534	99.60	gold quality
left testis	UBERON:0004533	99.59	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.39	gold quality
adenohypophysis	UBERON:0002196	99.28	gold quality
cerebellar hemisphere	UBERON:0002245	99.28	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.23	gold quality
cerebellar cortex	UBERON:0002129	99.21	gold quality
cingulate cortex	UBERON:0003027	99.13	gold quality
lower esophagus	UBERON:0013473	99.10	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.10	gold quality
anterior cingulate cortex	UBERON:0009835	99.09	gold quality
muscle layer of sigmoid colon	UBERON:0035805	99.06	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.05	gold quality
lower esophagus mucosa	UBERON:0035834	99.00	gold quality
right uterine tube	UBERON:0001302	98.99	gold quality
mucosa of stomach	UBERON:0001199	98.98	gold quality
popliteal artery	UBERON:0002250	98.98	gold quality
tibial artery	UBERON:0007610	98.98	gold quality
left ovary	UBERON:0002119	98.97	gold quality
tibial nerve	UBERON:0001323	98.94	gold quality
prefrontal cortex	UBERON:0000451	98.93	gold quality
right coronary artery	UBERON:0001625	98.91	gold quality
right ovary	UBERON:0002118	98.91	gold quality
apex of heart	UBERON:0002098	98.89	gold quality
ascending aorta	UBERON:0001496	98.87	gold quality
thoracic aorta	UBERON:0001515	98.87	gold quality
endocervix	UBERON:0000458	98.85	gold quality
descending thoracic aorta	UBERON:0002345	98.85	gold quality
left coronary artery	UBERON:0001626	98.84	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-124263	yes	922.29
E-MTAB-9221	yes	21.40
E-HCAD-9	yes	9.71
E-MTAB-9467	yes	4.43
E-HCAD-10	yes	3.57
E-MTAB-7606	no	685.25
E-GEOD-75367	no	146.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

38 targeting FKBP8, 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-12118	100.00	65.88	1270
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521

Literature-anchored findings (GeneRIF, showing 40)

• FKBP38 plays a role in TSC gene-dependent cell size regulation. (PMID:12894220)
• Bcl-2 interacts with FKBP38 through the unstructured loop, and the interaction appears to regulate phosphorylation in the loop of Bcl-2 (PMID:15733859)
• FKBP38 indirectly affects the subcellular distribution of calcineurin by interaction with typical calcineurin ligands, as exemplified by the anti-apoptotic protein Bcl-2. (PMID:15757646)
• Molecular model of the FK506-binding domain of FKBP38. (PMID:16604427)
• the complex consisting of NS5A, FKBP8, and Hsp90 plays an important role in HCV RNA replication (PMID:17024179)
• Data suggest that the peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. (PMID:17353276)
• FKBP38 is a co-chaperone of HERG and contributes via the Hsc70/Hsp90 chaperone system to the trafficking of wild type and mutant HERG potassium channels (PMID:17569659)
• FKBP38 functions to anchor the 26S proteasome at the organellar membrane (PMID:17573772)
• interaction between the catalytic FKBP38 domain and the N-terminal CaM domain activates FKBP38 and, as a consequence, also regulates Bcl-2. (PMID:17942410)
• findings suggest that FKBP38 is an endogenous inhibitor of mTOR, whose inhibitory activity is antagonized by Rheb in response to growth factor stimulation and nutrient availability (PMID:17991864)
• These results suggest that specific interaction of NS5A with FKBP8 in the cytoplasmic compartment plays a crucial role in the replication of HCV. (PMID:18216108)
• FKBP38 is a bona fide effector of Rheb and the ability to interact with FKBP38 is important for Rheb as an activator of mTOR (PMID:18658153)
• neither TCTP nor FKBP38 regulates mTORC1 signaling. (PMID:18676370)
• FKBP38 plays only a very minor, if any, role in mTORC1 activation. (PMID:19222999)
• Data indicate that PHD2 protein stability is regulated by a ubiquitin-independent proteasomal pathway involving FKBP38 as adaptor protein that mediates proteasomal interaction. (PMID:19546213)
• Rheb GTPase controls apoptosis by regulating interaction of FKBP38 with Bcl-2 and Bcl-XL (PMID:20048149)
• FKBP38 is a key player in regulating the function of Bcl-2 by antagonizing caspase-dependent degradation through the direct interaction with the flexible loop domain of Bcl-2, which contains the caspase cleavage site (PMID:20139069)
• this charge-sensitive site in the FKBP domain participates in the regulation of FKBP38 function by enabling electrostatic interactions with ligand proteins and/or salt ions such as Ca(2+) (PMID:20140889)
• novel insights into the structural arrangement of FKBP38/calmodulin complex (PMID:20707607)
• These results demonstrate that FKBP38 is a novel regulator of the oncogenic protein PRL-3 abundance and that alteration in the stability of PRL-3 can have a dramatic impact on cell proliferation. (PMID:21320469)
• a dual mechanism for PA activation of mTORC1: PA displaces FKBP38 from mTOR and allosterically stimulates the catalytic activity of mTORC1. (PMID:21737445)
• Data support a dual role for FKBP38 in regulating CFTR synthesis and post-translational folding. (PMID:22030396)
• FK506 binding protein 8 peptidylprolyl isomerase activity manages a late stage of cystic fibrosis transmembrane conductance regulator (CFTR) folding and stability (PMID:22474283)
• The derived structure model of the complex between Bcl-2 and the FKBP38 catalytic domain features both electrostatic and hydrophobic intermolecular contacts and provides a rationale for the regulation of the FKBP38/Bcl-2 interaction by Ca(2+). (PMID:22523079)
• Overexpression of permanently active S100P in Huh-7 cells inhibited the interaction of FKBP38 with Bcl-2, resulting in the suppression of Bcl-2 stability (PMID:24295050)
• Regulation of CLC-1 chloride channel biosynthesis by FKBP8 and Hsp90beta as a molecular model for myotonia congenita has been described. (PMID:27580824)
• FKBP8 binding to Hsp90 did not substantially influence its ATPase activity (PMID:28278223)
• Co-expression of FKBP8 with LC3A profoundly induces Parkin-independent mitophagy. Strikingly, even when acting as a mitophagy receptor, FKBP8 avoids degradation by escaping from mitochondria. In summary, this study identifies novel roles for FKBP8 and LC3A, which act together to induce mitophagy. (PMID:28381481)
• Cycling between the inactive GDP- and the active GTP-bound state modulates the backbone dynamics of a C-terminal truncated form, RhebDeltaCT, which is suggested to influence its interactions. We further investigated the interactions between RhebDeltaCT and the proposed Rheb-binding domain of the regulatory protein FKBP38. (PMID:29194576)
• This study identifies FK506 binding protein 8 (FKBP8) as a candidate interacting protein of VISA through the yeast two-hybrid technique. A novel function of FKBP8 in innate immunity antiviral signaling regulation was revealed in this study. (PMID:30267576)
• Results demonstrated that FKBP8 physically interacts and co-localizes with SPP in endoplasmic reticulum, supporting that FKBP8 is a bona fide substrate of SPP. Also, the data support the involvement of inverse regulation of FKBP8 and mTOR signaling in SPP-enhanced tumorigenicity. (PMID:30348988)
• FKBP8 Enhances Protein Stability of the CLC-1 Chloride Channel at the Plasma Membrane (PMID:30487393)
• FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions. (PMID:31908024)
• FKBP8 variants are risk factors for spina bifida. (PMID:32969478)
• FKBP8 is a novel molecule that participates in the regulation of the autophagic pathway. (PMID:35090967)
• Tacrolimus-binding protein FKBP8 directs myosin light chain kinase-dependent barrier regulation and is a potential therapeutic target in Crohn’s disease. (PMID:35537812)
• [Fkbp38 deletion induces premature ovarian insufficiency in mice by activating mTOR signaling and inducing granulosa cell apoptosis]. (PMID:36504053)
• FKBP38 Regulates Self-Renewal and Survival of GBM Neurospheres. (PMID:37947640)
• FKBP38 suppresses endometrial cancer cell proliferation and metastasis by inhibiting the mTOR pathway. (PMID:38218360)
• GPX4 inhibits apoptosis of thyroid cancer cells through regulating the FKBP8/Bcl-2 axis. (PMID:38250761)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	fkbp8	ENSDARG00000001734
mus_musculus	Fkbp8	ENSMUSG00000019428
rattus_norvegicus	Fkbp8	ENSRNOG00000058359
drosophila_melanogaster	Fkbp39	FBGN0013269
caenorhabditis_elegans		WBGENE00001429
caenorhabditis_elegans	fkb-5	WBGENE00001430

Paralogs (18): FKBP4 (ENSG00000004478), FKBP6 (ENSG00000077800), FKBP7 (ENSG00000079150), FKBP1A (ENSG00000088832), FKBP5 (ENSG00000096060), FKBP3 (ENSG00000100442), FKBP14 (ENSG00000106080), FKBP15 (ENSG00000119321), FKBP1B (ENSG00000119782), FKBP9 (ENSG00000122642), TTC9 (ENSG00000133985), FKBP11 (ENSG00000134285), FKBP10 (ENSG00000141756), TTC9C (ENSG00000162222), FKBP2 (ENSG00000173486), TTC9B (ENSG00000174521), FKBP1C (ENSG00000198225), FKBPL (ENSG00000204315)

Protein

Protein identifiers

Peptidyl-prolyl cis-trans isomerase FKBP8 — Q14318 (reviewed: Q14318)

Alternative names: 38 kDa FK506-binding protein, FK506-binding protein 8, FKBPR38, Rotamase

All UniProt accessions (10): Q14318, A0A0A0MTJ1, M0R1Q0, M0R1S6, M0R2K9, M0R2Q6, M0R304, U3KQ64, U3KQI1, V9GZ05

UniProt curated annotations — full annotation on UniProt →

Function. Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium. Seems to act as a chaperone for BCL2, targets it to the mitochondria and modulates its phosphorylation state. The BCL2/FKBP8/calmodulin/calcium complex probably interferes with the binding of BCL2 to its targets. The active form of FKBP8 may therefore play a role in the regulation of apoptosis. Involved in the inhibition of viral infection by influenza A viruses (IAV).

Subunit / interactions. Homomultimers or heteromultimers (Potential). Forms heterodimer with calmodulin. When activated by calmodulin and calcium, interacts with the BH4 domain of BCL2 and weakly with BCL2L1/BCLX isoform Bcl-X(L). Does not bind and inhibit calcineurin. Interacts with ZFYVE27; may negatively regulate ZFYVE27 phosphorylation. (Microbial infection) Interacts with hepatitis C/HCV protein NS5A.

Subcellular location. Mitochondrion. Mitochondrion membrane Mitochondrion membrane Mitochondrion membrane.

Tissue specificity. Widely expressed. Highest levels seen in the brain. Highly abundant in the retina.

Post-translational modifications. Ubiquitinated by PRKN during mitophagy, leading to its degradation and enhancement of mitophagy. Deubiquitinated by USP30.

Miscellaneous. Binds the immunosuppressant FK506 only in its calmodulin/calcium activated form. Interacts with BCL2L1/BCLX.

Isoforms (3)

UniProt ID	Names	Canonical?
Q14318-1	1	yes
Q14318-2	2
Q14318-3	3

RefSeq proteins (2): NP_001295302, NP_036313* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001179	PPIase_FKBP_dom	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR046357	PPIase_dom_sf	Homologous_superfamily
IPR050754	FKBP4/5/8-like	Family

Pfam: PF00254, PF13432

Enzyme classification (BRENDA):

• EC 5.2.1.8 — peptidylprolyl isomerase (BRENDA: 69 organisms, 374 substrates, 222 inhibitors, 24 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-SUCCINYL-ALA-GLU-(TRANS)-PRO-PHE-4-NITROANILID	0.17–0.7	5
N-SUCCINYL-ALA-ALA-(CIS)-PRO-PHE-4-NITROANILIDE	0.104–0.814	2
RNASE T1	0.0004–0.0006	2
SUCCINYL-ALA-ALA-PRO-PHE 4-NITROANILIDE	0.451–1.247	2
SUCCINYL-ALA-LYS-PRO-PHE-4-NITROANILIDE	0.585–0.788	2
ALA-GLY-PSI[CS-N]-PRO-PHE-4-NITROANILIDE	0.53	1
N-SUCCINYL-ALA-LEU-(CIS)-PRO-PHE-4-NITROANILIDE	0.059	1
SUCCINYL-ALA-GLU-PRO-PHE-7-AMIDO-4-METHYLCOUMARI	0.12	1
TRYWNAKMK-(CIS)-PFIFGA	2	1
SUCCINYL-ALA-ALA-(CIS)-PRO-LYS-4-METHYLCOUMARIN-	—	0
SUCCINYL-ALA-ALA-(CIS)-PRO-PHE 4-METHYLCOUMARIN	—	0

Catalyzed reactions (Rhea), 1 shown:

• [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0) (RHEA:16237)

UniProt features (51 total): helix 12, cross-link 11, strand 7, sequence conflict 3, repeat 3, splice variant 2, mutagenesis site 2, turn 2, binding site 2, chain 1, transmembrane region 1, modified residue 1, domain 1, sequence variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3EY6	X-RAY DIFFRACTION	1.05
2AWG	X-RAY DIFFRACTION	1.6
5MGX	X-RAY DIFFRACTION	2.18
2D9F	SOLUTION NMR
2F2D	SOLUTION NMR
2MF9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14318-F1	81.09	0.65

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 (2): 149; 151

Post-translational modifications (12): 296, 249, 271, 273, 284, 307, 314, 334, 340, 348, 351, 352

Mutagenesis-validated functional residues (2):

Position	Phenotype
149	abolishes calcium-binding and reduces affinity for bcl2; when associated with asn-151.
151	abolishes calcium-binding and reduces affinity for bcl2; when associated with asn-149.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5689880	Ub-specific processing proteases

MSigDB gene sets: 176 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_GROWTH, PID_NFAT_3PATHWAY, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_DORSAL_VENTRAL_PATTERN_FORMATION, GOBP_MACROAUTOPHAGY, BROWNE_HCMV_INFECTION_48HR_DN, GOBP_POSITIVE_REGULATION_OF_BMP_SIGNALING_PATHWAY, GOBP_PROTEIN_MATURATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (21): negative regulation of protein phosphorylation (GO:0001933), protein folding (GO:0006457), apoptotic process (GO:0006915), smoothened signaling pathway (GO:0007224), regulation of gene expression (GO:0010468), dorsal/ventral neural tube patterning (GO:0021904), BMP signaling pathway (GO:0030509), positive regulation of BMP signaling pathway (GO:0030513), multicellular organism growth (GO:0035264), intracellular signal transduction (GO:0035556), camera-type eye development (GO:0043010), negative regulation of apoptotic process (GO:0043066), neuron fate specification (GO:0048665), protein localization to mitochondrion (GO:0070585), regulation of mitophagy (GO:1901524), cell fate specification (GO:0001708), signal transduction (GO:0007165), dorsal/ventral pattern formation (GO:0009953), neural tube development (GO:0021915), regulation of BMP signaling pathway (GO:0030510), regulation of macromolecule metabolic process (GO:0060255)

GO Molecular Function (8): peptidyl-prolyl cis-trans isomerase activity (GO:0003755), calmodulin binding (GO:0005516), identical protein binding (GO:0042802), protein folding chaperone (GO:0044183), metal ion binding (GO:0046872), disordered domain specific binding (GO:0097718), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (9): mitochondrion (GO:0005739), mitochondrial envelope (GO:0005740), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), endomembrane system (GO:0012505), membrane (GO:0016020), mitochondrial membrane (GO:0031966), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
cellular process	2
BMP signaling pathway	2
protein binding	2
intracellular membrane-bounded organelle	2
mitochondrion	2
organelle membrane	2
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
protein maturation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell surface receptor signaling pathway	1
gene expression	1
regulation of macromolecule biosynthetic process	1
dorsal/ventral pattern formation	1
neural tube patterning	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
regulation of BMP signaling pathway	1
positive regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
multicellular organismal process	1
developmental growth	1
intracellular anatomical structure	1
signal transduction	1
eye development	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cell fate specification	1
neuron fate commitment	1
protein localization to organelle	1
mitophagy	1
regulation of macroautophagy	1
regulation of autophagy of mitochondrion	1
cell fate commitment	1

Protein interactions and networks

STRING

3366 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FKBP8	RPTOR	Q8N122	994
FKBP8	MLST8	Q9BVC4	994
FKBP8	MAP1LC3A	Q9H492	989
FKBP8	AKT1S1	Q96B36	988
FKBP8	HSP90AA1	P07900	985
FKBP8	HSP90AB1	P08238	980
FKBP8	BCL2	P10415	979
FKBP8	DEPTOR	Q8TB45	955
FKBP8	RHEB	Q15382	931
FKBP8	GABARAP	O95166	917
FKBP8	MTOR	P42345	896
FKBP8	BCL2L13	Q9BXK5	809
FKBP8	FUNDC1	Q8IVP5	807
FKBP8	BCL2L1	Q07817	788
FKBP8	BNIP3	Q12983	749

IntAct

354 interactions, top by confidence:

A	B	Type	Score
	FKBP8	psi-mi:“MI:0915”(physical association)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EGFR	FKBP8	psi-mi:“MI:0915”(physical association)	0.680
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
FKBP8	ZFYVE27	psi-mi:“MI:0915”(physical association)	0.630
ZFYVE27	FKBP8	psi-mi:“MI:0915”(physical association)	0.630
FKBP8	FGF14	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	TMEM43	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	SCN3B	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	CYB561	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	TMEM254	psi-mi:“MI:0915”(physical association)	0.560
ZFPL1	FKBP8	psi-mi:“MI:0915”(physical association)	0.560
CXCR2	FKBP8	psi-mi:“MI:0915”(physical association)	0.560
	FKBP8	psi-mi:“MI:0915”(physical association)	0.560
PLN	FKBP8	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	ARL13B	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	RETREG3	psi-mi:“MI:0915”(physical association)	0.560
CYB561	FKBP8	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	CIDEB	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	TMX1	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	ELOVL4	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	JAGN1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (771): FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), ABCB7 (Co-fractionation), FKBP8 (Proximity Label-MS), FKBP8 (Proximity Label-MS), FKBP8 (Proximity Label-MS), FKBP8 (Proximity Label-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS), FKBP8 (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1F4, A0A0G2JXN2, A2AWP8, A2RRH5, C9J798, O43374, O70277, O95294, P04629, P59926, Q0GA42, Q13368, Q14318, Q16512, Q29RM4, Q2HY40, Q2T9P3, Q2TBA3, Q5BIM1, Q5M7W1, Q5R5M3, Q5R811, Q5T7P8, Q5XIS9, Q62746, Q6PFQ7, Q6PFY8, Q7TNM2, Q7TP90, Q7Z4K8, Q8BG60, Q8BHT7, Q8BQC3, Q8C6N3, Q8CIW5, Q8IZ69, Q8NCT1, Q920N2, Q92546, Q925B4

Diamond homologs: A4IFF3, A4IHU6, O35450, O35465, P26882, P53691, Q08752, Q14318, Q3B7U9, Q3V038, Q5RAP0, Q6DGG0, Q6MG81, Q6P5P3, Q7DMA9, Q810A3, Q8N5M4, Q8N6N2, Q92623, Q9BGT1, Q9CR16, Q9D6E4, Q9H3U1, O42123, P0C1J7, P48375, Q13451, Q5RF88, Q64378, Q6CF41, Q863A4, Q863A5, Q863A6, Q863A7, Q8WXU2, Q95L05, A5IGB8, D3ZQF4, O04287, O46638

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FKBP8	down-regulates	MTOR	binding
RHEB	down-regulates	FKBP8	binding
RHEB	“down-regulates activity”	FKBP8	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
response to endoplasmic reticulum stress	7	10.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
19:18532688:A:AC	donor_gain	1.0000
19:18532688:AG:A	donor_gain	1.0000
19:18532689:G:C	donor_gain	1.0000
19:18532792:TCGT:T	acceptor_gain	1.0000
19:18532793:CGT:C	acceptor_gain	1.0000
19:18532793:CGTC:C	acceptor_gain	1.0000
19:18532796:C:CC	acceptor_gain	1.0000
19:18532796:CT:C	acceptor_loss	1.0000
19:18533265:CTCA:C	donor_loss	1.0000
19:18533266:TCA:T	donor_loss	1.0000
19:18533267:CAC:C	donor_loss	1.0000
19:18533269:C:CA	donor_loss	1.0000
19:18537596:CCTA:C	donor_loss	1.0000
19:18537597:CTA:C	donor_loss	1.0000
19:18537598:TACC:T	donor_loss	1.0000
19:18537600:C:CT	donor_loss	1.0000
19:18537600:CCTTG:C	donor_gain	1.0000
19:18537771:CCA:C	acceptor_gain	1.0000
19:18537772:CAC:C	acceptor_gain	1.0000
19:18537774:C:CC	acceptor_gain	1.0000
19:18538211:GTCAC:G	donor_loss	1.0000
19:18538212:TCA:T	donor_loss	1.0000
19:18538214:ACCTT:A	donor_loss	1.0000
19:18538235:AG:A	donor_gain	1.0000
19:18538408:CCGCG:C	acceptor_gain	1.0000
19:18538409:CGCG:C	acceptor_gain	1.0000
19:18538412:G:GC	acceptor_gain	1.0000
19:18538434:CTG:C	acceptor_gain	1.0000
19:18538437:C:CC	acceptor_gain	1.0000
19:18539465:G:C	acceptor_gain	1.0000

AlphaMissense

2661 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:18532200:G:T	A403E	1.000
19:18532206:C:T	G401D	1.000
19:18532207:C:G	G401R	1.000
19:18532209:C:T	G400E	1.000
19:18532210:C:G	G400R	1.000
19:18532210:C:T	G400R	1.000
19:18532215:G:T	A398D	1.000
19:18532218:A:T	V397D	1.000
19:18532221:G:T	A396D	1.000
19:18532230:C:T	G393E	1.000
19:18532716:A:G	M367T	1.000
19:18532770:A:G	L349P	1.000
19:18532779:A:G	L346P	1.000
19:18533292:A:G	L333P	1.000
19:18533295:G:T	A332D	1.000
19:18533304:A:G	L329P	1.000
19:18537605:C:T	G313D	1.000
19:18537606:C:G	G313R	1.000
19:18537611:C:G	R311P	1.000
19:18537612:G:T	R311S	1.000
19:18537622:C:A	K307N	1.000
19:18537622:C:G	K307N	1.000
19:18537628:G:C	N305K	1.000
19:18537628:G:T	N305K	1.000
19:18537658:G:C	C295W	1.000
19:18537671:G:T	A291D	1.000
19:18537695:A:G	L283P	1.000
19:18537704:G:T	A280D	1.000
19:18537710:A:G	L278P	1.000
19:18537712:G:C	N277K	1.000

dbSNP variants (sampled 300 via entrez): RS1000577323 (19:18539096 A>G), RS1001120857 (19:18533492 A>G), RS1001215082 (19:18541218 C>T), RS1001324498 (19:18535661 T>C), RS1001682881 (19:18535812 G>A), RS1001863094 (19:18532890 G>T), RS1001909862 (19:18545337 G>A,T), RS1002103945 (19:18538584 G>A), RS1002198343 (19:18539985 GTTTT>G,GTTT,GTTTTT), RS1002399058 (19:18532580 G>A,C), RS1002507607 (19:18543800 C>G), RS1002888977 (19:18542484 G>A), RS1002919997 (19:18542644 C>A), RS1002974778 (19:18537574 C>G,T), RS1003002545 (19:18537827 C>T)

Disease associations

OMIM: gene MIM:604840 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
spina bifida	Moderate	Autosomal dominant

Mondo (1): spina bifida (MONDO:0008449)

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006431_4	Plasma parathyroid hormone levels	6.000000e-07
GCST008648_7	Urinary potassium excretion	6.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009283	potassium measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016135	Spinal Dysraphism	C10.500.680.800; C16.131.666.680.800

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291572 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Peptidyl-prolyl cis/trans isomerases

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
GPI-1046	Inhibitor	7.32	pKi
DM-CHX	Inhibitor	7.07	pKi

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	Kd	30.1	nM	CHEMBL5653589
7.52	ED50	30.1	nM	CHEMBL5653589
5.60	IC50	2500	nM	CHEMBL5558644
5.40	IC50	4000	nM	CHEMBL5558181

PubChem BioAssay actives

3 with measured affinity, of 5 total; 3 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148392: Binding affinity to human FKBP8 incubated for 45 mins by Kinobead based pull down assay	kd	0.0301	uM
methyl 2-[[2-[[5,6-bis(furan-2-yl)-1,2,4-triazin-3-yl]sulfanyl]acetyl]amino]-4,5-dimethylthiophene-3-carboxylate	2084023: Inhibition of GST-tagged human FKBP38 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	2.5000	uM
N,N’-bis(3-carbamoyl-4,5-dimethylthiophen-2-yl)pentanediamide	2084023: Inhibition of GST-tagged human FKBP38 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	ic50	4.0000	uM

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
Doxorubicin	increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
4-oxoretinoic acid	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
tetrahydropalmatine	decreases expression	1
beta-lapachone	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
ochratoxin A	increases acetylation, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
LDN 193189	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Pioglitazone	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Atrazine	increases expression	1
Cannabidiol	affects cotreatment, decreases expression	1
Clozapine	decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Dinitrochlorobenzene	affects binding	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5524496	Binding	Inhibition of GST-tagged human FKBP38 expressed in Escherichia coli BL21 (DE3) using NH2-EDASRMEEVD-COOH peptide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by Alpha Screen assay	Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction. — Eur J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SN63	HAP1 FKBP8 (-) 1	Cancer cell line	Male
CVCL_SN64	HAP1 FKBP8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07027020	PHASE3	RECRUITING	Efficacy of Intravesical Oxybutynin in Children With Neurogenic Bladder Dysfunction
NCT00359775	PHASE2	COMPLETED	Coping Skills Training (CST) for Children With Chronic Health Conditions
NCT00378664	PHASE2	COMPLETED	Lumbar to Sacral Ventral Nerve Re-Routing
NCT00031122	Not specified	UNKNOWN	Study of Genetic Risk Factors for Spina Bifida and Anencephaly
NCT00655681	Not specified	COMPLETED	Prevention of Post Operative Bone Loss in Children
NCT00720161	Not specified	COMPLETED	Metformin in Children With Motor Deficit
NCT00866112	Not specified	COMPLETED	A Randomized Exercise Trial for Wheelchair Users
NCT00891891	Not specified	ACTIVE_NOT_RECRUITING	Psychosocial Adjustment of Adolescents With Spina Bifida
NCT00951509	Not specified	COMPLETED	Virtual Reality Based Testing of Power Wheelchair Driving Skills
NCT01096459	Not specified	WITHDRAWN	Nerve Rerouting Treatment for Neurogenic Bladder in Spina Bifida
NCT01133288	Not specified	TERMINATED	Yulex Glove Prospective Study in Spina Bifida
NCT01263392	Not specified	COMPLETED	Comparing Urinary Tract Infections in Children With Spina Bifida Using Two Types of Catheters for Catheterization
NCT01302314	Not specified	COMPLETED	Cognitive Rehabilitation in Patients With Spina Bifida
NCT01961557	Not specified	COMPLETED	Evaluating a New Knee-Ankle-Foot Brace to Improve Gait in Children With Movement Disorders
NCT02341950	Not specified	COMPLETED	Clinical Trial of a Serious Game for Individuals With SCI/D
NCT02361450	Not specified	COMPLETED	Retrograde Colonic Irrigation to Manage Spina Bifida Functional Digestive Sequelae: a Multicenter, Prospective, Randomized Controlled Trial
NCT02386228	Not specified	TERMINATED	Micro Ribonucleic Acid (miRNA) Markers of Hydrocephalus in Intraventricular Hemorrhage (IVH)
NCT02428673	Not specified	COMPLETED	Effects of Standing on Non-Ambulatory Children With Neuromuscular Conditions
NCT02440984	Not specified	COMPLETED	Anorectal Dysfunction in Patients Suffering From Spina Bifida : From Clinic to Neuro-epithelial Function (ANOSPIN)
NCT02522507	Not specified	COMPLETED	A Peer E-mentoring Intervention to Improve Employment
NCT02592291	Not specified	RECRUITING	Mobile Health Self-Management and Support System for Chronic and Complex Health Conditions
NCT02682043	Not specified	COMPLETED	Parental Perspectives of Using Toy Cars on Social Interactions of Preschool Children With Mobility Impairments
NCT02685813	Not specified	UNKNOWN	Incidence of Pregnancies and Births With Spina Bifida in Denmark in 2008-2014
NCT02852317	Not specified	COMPLETED	Urinary Markers of Detrusor Overactivity in Spina Bifida Patients
NCT02854150	Not specified	COMPLETED	Improving Genetic Counseling for Patients With Spina Bifida Using Next Generation Sequencing
NCT02938130	Not specified	COMPLETED	The Impact of Community-based Wellness Programs on The Triple Aim
NCT03045276	Not specified	COMPLETED	Urological and Renal Disease Engaging Adolescents in Adherence Collaborative Trial
NCT03061084	Not specified	UNKNOWN	Prospective Cohort of Transitional Urology Patients
NCT03090633	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Repair of Isolated Fetal Spina Bifida
NCT03121651	Not specified	COMPLETED	Medication Management Among Individuals With Neurodevelopmental Disabilities
NCT03135145	Not specified	COMPLETED	Post-operative Lite Run Study
NCT03148301	Not specified	COMPLETED	Spina Bifida in Daily Life: an Exploratory Study
NCT03188107	Not specified	UNKNOWN	Interrater Reliability of Infant Motor Profile
NCT03410667	Not specified	ACTIVE_NOT_RECRUITING	Incontinence and Quality of Life in Children With Spina Bifida
NCT03466996	Not specified	COMPLETED	Telemedicine in Spina Bifida Transition: A Pilot Study
NCT03523806	Not specified	UNKNOWN	Children and Teens in Charge of Their Health
NCT03543995	Not specified	COMPLETED	The Relationship Between Nocturnal Enuresis And Spina Bifida Occulta
NCT03573726	Not specified	COMPLETED	Use of a Diurnal Indwelling Urethral Catheter to Improve Quality of Life
NCT03698721	Not specified	NOT_YET_RECRUITING	Urothelium Tissue Engineering Using Biopsies From Transurethral Resection of Prostate
NCT03797378	Not specified	COMPLETED	Movement-2-Music: Lakeshore Examination of Activity, Disability, and Exercise Response Study