KLB

UniProt ID: Q86Z14
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

KLB encodes beta-Klotho, a glycosylated single-pass type III plasma-membrane protein whose tandem extracellular glycoside-hydrolase-like domains have lost essential catalytic residues and instead form a high-affinity recognition surface for the endocrine fibroblast growth factors FGF19 and FGF21. KLB associates with FGFR4 and FGFR1-family receptors to assemble ligand-responsive receptor complexes: the KLB ectodomain supplies ligand specificity while the FGFR supplies intracellular tyrosine-kinase signaling. In liver, FGF19-KLB-FGFR4 signaling represses CYP7A1 and limits bile-acid synthesis; KLB also enables tissue-selective FGF21 metabolic signaling.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004553 hydrolase activity, hydrolyzing O-glycosyl compounds
IEA
GO_REF:0000002
REMOVE
Summary: InterPro transferred glycoside-hydrolase activity from the ancestral GH1-like fold.
Reason: Human KLB is a receptor-like pseudoenzyme. Each tandem GH-like domain lacks one essential catalytic glutamate, and the human structure explicitly concludes that neither domain can function as an active glycoside hydrolase.
Supporting Evidence:
PMID:29342135
The first glutamate in D1 is replaced by N241, whereas the second glutamate in D2 is replaced by A889, indicating that neither GH domain in Ξ²-Klotho can function as an active glycoside-hydrolase enzyme.
GO:0005886 plasma membrane
IEA
GO_REF:0000044
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002
REMOVE
Summary: InterPro inferred carbohydrate metabolism from KLB glycoside-hydrolase-like domains.
Reason: The transferred process rests on an enzymatic interpretation contradicted by the human structure. KLB influences systemic metabolism through endocrine-FGF receptor signaling, not by demonstrated carbohydrate hydrolysis; specific signaling and bile-acid regulatory terms capture the supported biology.
Supporting Evidence:
PMID:29342135
The first glutamate in D1 is replaced by N241, whereas the second glutamate in D2 is replaced by A889, indicating that neither GH domain in Ξ²-Klotho can function as an active glycoside-hydrolase enzyme.
GO:0017134 fibroblast growth factor binding
IEA
GO_REF:0000117
ACCEPT
Summary: KLB directly recognizes endocrine FGFs through its extracellular tandem GH-like domains.
Reason: Biochemical truncation, chimera, binding, and human structural experiments directly establish KLB binding to FGF19 and FGF21.
Supporting Evidence:
PMID:29342135
FGF21 binds with high affinity, KD = 43.5 nM
GO:0005515 protein binding
IPI
PMID:19059246
FGF21 N- and C-termini play different roles in receptor inte...
MODIFY
Summary: The cited study directly shows binding of the FGF21 carboxyl terminus to beta-Klotho.
Reason: Generic protein binding obscures the informative molecular activity demonstrated by the experiment. The annotation should use fibroblast growth factor binding.
Proposed replacements: fibroblast growth factor binding
Supporting Evidence:
PMID:19059246
FGF21 binds directly to beta-Klotho through its C-terminus.
GO:0005104 fibroblast growth factor receptor binding
IPI
PMID:17627937
Liver-specific activities of FGF19 require Klotho beta.
ACCEPT
Summary: KLB is required for assembly and signaling of the FGF19-FGFR4 receptor complex.
Reason: The experimental source defines KLB as an FGFR4 coreceptor required for FGF19 binding, intracellular signaling, and downstream gene regulation. Human structural work independently measures KLB-FGFR1c association.
Supporting Evidence:
PMID:17627937
KLB is required for FGF19 binding to FGFR4
PMID:29342135
FGFR1c extracellular region to sKLB
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-109699
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1307955
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-1307963
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2316434
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-2400009
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654151
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654163
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654169
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654418
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654422
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654423
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654425
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654426
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654428
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654566
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654651
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654653
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654655
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654658
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654659
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654662
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654663
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654664
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654667
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654669
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654684
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654714
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654717
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5654734
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0005886 plasma membrane
TAS
Reactome:R-HSA-5672965
ACCEPT
Summary: KLB is a glycosylated single-pass type III cell-surface protein; plasma-membrane placement is integral to its endocrine-FGF receptor-complex function.
Reason: The reviewed UniProt record and the membrane-associated KLB-FGFR complexes represented by Reactome consistently support this cellular-component annotation.
Supporting Evidence:
file:human/KLB/KLB-uniprot.txt
Cell membrane {ECO:0000305}; Single-pass type III
GO:0017134 fibroblast growth factor binding
IPI
PMID:19117008
Different roles of N- and C- termini in the functional activ...
ACCEPT
Summary: KLB directly recognizes endocrine FGFs through its extracellular tandem GH-like domains.
Reason: Biochemical truncation, chimera, binding, and human structural experiments directly establish KLB binding to FGF19 and FGF21.
Supporting Evidence:
PMID:19117008
interaction with the co-receptor involves the C-terminus
GO:0017134 fibroblast growth factor binding
IPI
PMID:18829467
C-terminal tail of FGF19 determines its specificity toward K...
ACCEPT
Summary: KLB directly recognizes endocrine FGFs through its extracellular tandem GH-like domains.
Reason: Biochemical truncation, chimera, binding, and human structural experiments directly establish KLB binding to FGF19 and FGF21.
Supporting Evidence:
PMID:18829467
C-terminal tail of FGF19 as a region necessary for its recognition of Klotho family proteins
GO:0015026 coreceptor activity
IDA
PMID:29342135
Structures of Ξ²-klotho reveal a 'zip code'-like mechanism fo...
NEW
Summary: Human structural, binding, and cell-signaling experiments establish KLB as the ligand-recognition component of endocrine-FGF receptor complexes.
Reason: KLB combines with FGF ligands and FGFRs to enable receptor activation while lacking its own intracellular catalytic domain. Coreceptor activity captures this molecular role more informatively than generic binding terms.
Supporting Evidence:
PMID:29342135
In this model, Ξ²-Klotho functions as a primary high affinity receptor for FGF21, whereas FGFR1c functions as a catalytic subunit that mediates receptor dimerization and intracellular signaling.
file:human/KLB/KLB-deep-research-manual.md
Evidence conclusion: KLB is an endocrine-FGF coreceptor at the plasma membrane.
GO:0008543 fibroblast growth factor receptor signaling pathway
IMP
PMID:29342135
Structures of Ξ²-klotho reveal a 'zip code'-like mechanism fo...
NEW
Summary: KLB is required for FGF21-dependent FGFR1c activation and for FGF19-FGFR4 signaling.
Reason: Cell experiments comparing FGFR1c with and without KLB, together with KLB binding-site mutants, directly show that KLB is required for endocrine-FGF-induced receptor phosphorylation and downstream signaling.
Supporting Evidence:
PMID:29342135
Ξ²-Klotho is required for FGFR1c-mediated signaling induced by FGF21.
GO:0070858 negative regulation of bile acid biosynthetic process
ISS
PMID:17627937
Liver-specific activities of FGF19 require Klotho beta.
NEW
Summary: The conserved FGF19-KLB-FGFR4 liver pathway represses CYP7A1, the rate-limiting enzyme in bile-acid synthesis.
Reason: The physiological CYP7A1 repression experiment is in mouse, so ISS is used for conservative transfer to human KLB rather than claiming direct human perturbation evidence.
Supporting Evidence:
PMID:17627937
FGF19 injection triggers liver-specific induction of c-Fos and repression of CYP7A1.

Core Functions

At the plasma membrane, KLB acts as the extracellular ligand-recognition and coreceptor component of endocrine-FGF receptor complexes. Its repurposed tandem GH-like domains bind FGF19 and FGF21, and KLB association with FGFR4 or FGFR1-family receptors permits ligand-dependent receptor activation. In the liver, the FGF19-KLB-FGFR4 arm represses CYP7A1 and limits bile-acid synthesis.

Supporting Evidence:
  • PMID:29342135
    In this model, Ξ²-Klotho functions as a primary high affinity receptor for FGF21, whereas FGFR1c functions as a catalytic subunit that mediates receptor dimerization and intracellular signaling.
  • PMID:17627937
    KLB is required for FGF19 binding to FGFR4, intracellular signaling, and downstream modulation of gene expression.

References

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Suggested Questions for Experts

Q: How do endogenous KLB-FGFR stoichiometry and complex-assembly kinetics differ between human liver, adipose tissue, and nervous-system target cells?

Q: Which KLB residues selectively distinguish FGF19 from FGF21 while preserving FGFR association and cell-surface expression?

Q: Does either repurposed GH-like domain retain noncanonical catalytic chemistry under physiological conditions?

Suggested Experiments

Experiment: Create structure-guided KLB variants that selectively disrupt FGF19/FGF21 site 1, site 2, or FGFR binding; verify matched surface expression and test ligand binding, FGFR phosphorylation, MAPK signaling, and rescue in KLB-null human hepatocyte and adipocyte models.

Hypothesis: KLB uses separable surfaces for endocrine-FGF recognition and FGFR association.

Type: Separation-of-function mutagenesis and receptor-signaling rescue

Experiment: Quantify endogenous KLB-FGFR1c/FGFR4 complexes before and after FGF19 or FGF21 stimulation in primary human hepatocytes and adipocytes using calibrated proximity imaging, cross-linking mass spectrometry, and receptor-phosphorylation time courses.

Hypothesis: Native KLB-FGFR complex stoichiometry determines tissue-selective endocrine-FGF responses.

Type: Endogenous receptor-complex stoichiometry and signaling kinetics

Experiment: Screen purified glycosylated human KLB ectodomain against a chemically diverse glycan panel with mass-spectrometric product detection, using active GH1 enzymes as positive controls and KLB ligand-binding mutants to separate receptor binding from any residual chemistry.

Hypothesis: KLB is catalytically inert despite retaining two GH1-like folds.

Type: Pseudoenzyme catalytic-function screen

Knowledge Gaps

What is not known β€” curated, literature-grounded statements of the open unknowns (the inverse of core functions).

Gap: The endogenous stoichiometry and ligand-dependent assembly sequence of KLB-FGFR complexes in human target tissues remain incompletely resolved.

OPEN BIOLOGY MF_DARK

What is known: Structures and transfected-cell assays establish the binding interfaces, but do not determine native receptor abundance or assembly kinetics in hepatocytes, adipocytes, or neurons.

Significance: Native complex architecture is needed to understand tissue selectivity and differences between FGF19 and FGF21 signaling.

What would resolve it: Measure endogenous KLB-FGFR proximity, stoichiometry, and ligand-dependent dynamics in primary human target cells using quantitative single-molecule imaging and orthogonal cross-linking mass spectrometry.

Provenance (the field's own admissions):

Gap: It is unknown whether either KLB GH-like domain retains any physiologically relevant residual chemistry despite loss of an essential catalytic glutamate.

OPEN BIOLOGY MF_DARK

What is known: The human structure establishes that canonical GH1 catalysis is impossible, but a targeted search for noncanonical chemistry has not been reported in the evidence set.

Significance: Resolving this would distinguish a fully repurposed pseudoenzyme from a receptor that retains unusual catalytic activity.

What would resolve it: Test purified, correctly glycosylated KLB ectodomain against broad glycan libraries with sensitive product detection, catalytic-residue controls, and ligand-binding-defective separation-of-function mutants.

Provenance (the field's own admissions):

Deep Research

Manual

(KLB-deep-research-manual.md)

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πŸ“š Additional Documentation

Notes

(KLB-notes.md)

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