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Different roles of N‐ and C‐ termini in the functional activity of FGF21
Abstract
Fibroblast growth factor 21 is a member of endocrine FGFs subfamily, along with FGF19 and FGF23. It is emerging as a novel regulator with beneficial effects on a variety of metabolic parameters, including glucose and lipid control. FGF21 activity depends on membrane protein βKlotho that physically complexes with various FGF receptors, thus conferring them the ability to bind FGF21 and activate downstream signaling pathways. FGF21, like other FGFs, folds to a β‐trefoil‐like core region, with disordered N‐ and C‐termini. In order to investigate their role in the activity of FGF21, we have constructed a series of deletion mutants and tested them for their ability to (1) bind βKlotho, analyzed by surface plasmon resonance spectroscopy (2) signal through MAPK phosphorylation and inhibit apoptosis in 3T3‐L1/βKlotho fibroblasts (3) stimulate GLUT1 mRNA upregulation and glucose uptake in 3T3‐L1 adipocytes. Binding studies with βKlotho revealed that the interaction with the co‐receptor involves the C‐terminus, as progressive removal of amino acids from the carboxy end decreased affinity for βKlotho. By contrast, removal of up to 17 amino acids from the N‐terminus had no effect on the interaction with βKlotho. Terminal deletions had greater effect on function, as deletions of six amino acids from the amino‐terminus and only four from the carboxy‐terminus each significantly impacted activity (10‐fold). Of the extreme terminal truncations, with no detectable activity, ΔN17 acted as competitive antagonist while ΔC20 did not. Our structure/function studies show that the C‐terminus is important for βKlotho interaction whereas the N‐terminus likely interacts directly with FGF receptors. J. Cell. Physiol. 219: 227–234, 2009. © 2008 Wiley‐Liss, Inc.
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In the citing paper
“FGF21 is also subject to proteolytic cleavage by the serine proteases fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV)42,43.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [44]
In the citing paper
“The deletion of these 10 residues on the C terminus of human FGF21 disrupts its ability to interact with β-klotho and signal to target tissues (89, 144).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [89]
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Metadata
- Authors
- Micanovic, R., Raches, D. W., Dunbar, J. D., Driver, D. A., Bina, H. A., Dickinson, C. D., & Kharitonenkov, A.
- Affiliations
- Eli Lilly (United States) (US)
- Corresponding author
- Micanovic, Radmila
- Venue
- Journal of Cellular Physiology
- Publisher
- Wiley
- Published
- 2008-12-30
- Volume
- 219
- Issue
- 2
- Pages
- 227-234
- ISSN
- 0021-9541 (ISSN-L)
- 1097-4652
- OpenAlex
- W2074337024
- Cited by
- 146
- References
- 39
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 13 · 2022: 3 · 2021: 10 · 2020: 10 · 2019: 7 · 2018: 14 · 2017: 11 · 2016: 12 · 2015: 9 · 2014: 3 · 2013: 5 · 2012: 16
- FWCI
- 1.78
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Cellular Physiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
- Keywords
- FGF21, β-Klotho, N-terminus, C-terminus, structure functions, fibroblast growth factor receptor, protein-protein interaction, β-trefoil fold, MAPK signaling, GLUT1, glucose uptake, adipocytes, 3T3-L1 fibroblasts, competitive antagonists
- MeSH terms
- Fibroblast Growth Factor-23, Klotho Proteins, Animals, Fibroblast Growth Factors, Fibroblasts, Membrane Proteins, Mutation, 3T3 Cells, Apoptosis, Protein Structure, Secondary, Protein Structure, Tertiary, Receptors, Fibroblast Growth Factor, Adipocytes, Surface Plasmon Resonance, Mitogen-Activated Protein Kinases, MAP Kinase Signaling System, Glucose Transporter Type 1, Mice
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