In:
Journal of Cellular Physiology, Wiley, Vol. 219, No. 2 ( 2009-05), p. 227-234
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.
Type of Medium:
Online Resource
ISSN:
0021-9541
,
1097-4652
Language:
English
Publisher:
Wiley
Publication Date:
2009
detail.hit.zdb_id:
1478143-8
SSG:
12
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