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A systematic dissection of sequence elements determining ?-Klotho and FGF interaction and signaling.

ABSTRACT: Endocrine fibroblast growth factors (FGFs) require Klotho transmembrane proteins as necessary co-receptors to activate FGF receptor (FGFR) signaling. In particular, FGF19 and FGF21 function through ?-Klotho to regulate glucose and lipid metabolism. Recent research has focused on elucidating how these two FGFs interact with ?-Klotho and FGFRs to activate downstream signaling. In this study, using hydrogen deuterium exchange coupled to mass spectrometry (HDX-MS), we identified regions on the ?-Klotho protein that likely participate in ligand interaction, and vice versa. Alanine and arginine mutagenesis were carried out to further probe the contributions of individual residues to receptor/ligand interactions. Using biochemical and cell-based signaling assays with full-length proteins, we show that both the KL1 and KL2 domains of ?-Klotho participate in ligand interaction, and these binding sites on ?-Klotho are shared by FGF19 and FGF21. In addition, we show that two highly conserved regions in the C-terminal tail of FGF19 and FGF21 are responsible for interaction with the co-receptor. Our results are consistent with recent publications on the crystal structures of the Klotho proteins and provide insight into how endocrine FGFs interact with co-receptors for signal transduction.

SUBMITTER: Shi SY

PROVIDER: S-EPMC6056499 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A systematic dissection of sequence elements determining β-Klotho and FGF interaction and signaling.

Shi Sally Yu SY Lu Ya-Wen YW Richardson Jason J Min Xiaoshan X Weiszmann Jennifer J Richards William G WG Wang Zhulun Z Zhang Zhongqi Z Zhang Jun J Li Yang Y

Scientific reports 20180723 1

Endocrine fibroblast growth factors (FGFs) require Klotho transmembrane proteins as necessary co-receptors to activate FGF receptor (FGFR) signaling. In particular, FGF19 and FGF21 function through β-Klotho to regulate glucose and lipid metabolism. Recent research has focused on elucidating how these two FGFs interact with β-Klotho and FGFRs to activate downstream signaling. In this study, using hydrogen deuterium exchange coupled to mass spectrometry (HDX-MS), we identified regions on the β-Klo ...[more]

PMID: 30038432

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Project description:BackgroundConus, a highly diverse species of venomous predators, has attracted significant attention in neuroscience and new drug development due to their rich collection of neuroactive peptides called conotoxins. Recent advancements in transcriptome, proteome, and genome analyses have facilitated the identification of conotoxins within Conus' venom glands, providing insights into the genetic features and evolutionary patterns of conotoxin genes. However, the underlying mechanism behind the extraordinary hypervariability of conotoxins remains largely unknown.ResultsWe analyzed the transcriptomes of 34 Conus species, examining various tissues such as the venom duct, venom bulb, and salivary gland, leading to the identification of conotoxin genes. Genetic variation analysis revealed that a subset of these genes (15.78% of the total) in Conus species underwent positive selection (Ka/Ks > 1, p < 0.01). Additionally, we reassembled and annotated the genome of C. betulinus, uncovering 221 conotoxin-encoding genes. These genes primarily consisted of three exons, with a significant portion showing high transcriptional activity in the venom ducts. Importantly, the flanking regions and adjacent introns of conotoxin genes exhibited a higher prevalence of transposon elements, suggesting their potential contribution to the extensive variability observed in conotoxins. Furthermore, we detected genome duplication in C. betulinus, which likely contributed to the expansion of conotoxin gene numbers. Interestingly, our study also provided evidence of introgression among Conus species, indicating that interspecies hybridization may have played a role in shaping the evolution of diverse conotoxin genes.ConclusionsThis study highlights the impact of adaptive evolution and introgressive hybridization on the genetic diversity of conotoxin genes and the evolution of Conus. We also propose a hypothesis suggesting that transposable elements might significantly contribute to the remarkable diversity observed in conotoxins. These findings not only enhance our understanding of peptide genetic diversity but also present a novel approach for peptide bioengineering.

Dataset Information

A systematic dissection of sequence elements determining ?-Klotho and FGF interaction and signaling.

Publications

A systematic dissection of sequence elements determining β-Klotho and FGF interaction and signaling.

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