Identification of a second Klotho interaction site in the C terminus of FGF23

Agrawal, Archita; Ni, Pu; Agoro, Rafiou; White, Kenneth E.; DiMarchi, Richard D.

doi:10.1016/j.celrep.2020.108665

Cited by 16 publications

(19 citation statements)

References 34 publications

(76 reference statements)

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“…The crystal structures of KLA with FGF23 are depicted in Figure 5 A [ 6 , 172 ]. This crystal structure supports the notion that FGF23 binds to FGFRs (FGFR 1c, 3c, and 4) in the presence of a co-receptor, KLA [ 68 , 210 ]. Furthermore, the KLA crystal structure shows that there are 2 extracellular domains, KL1 (E34 to F506) and KL2 (L515 to S950), in KLA [ 211 ].…”

Section: Klotho Proteinssupporting

confidence: 80%

Section: Klotho Proteinsmentioning

confidence: 99%

“…The crystal structure of KLA reveals that it binds tightly to FGF23 and FGFR1c [ 68 , 69 ]. In this binding process, KLA increases the proximity of FGF23 and the receptor (FGFR1c), thereby increasing the binding affinity of FGF23 with the receptor FGFR1c [ 68 , 69 ]. In this complex, FGF23: FGFR1c: KLA, KLA exists in an extended conformation adopting a triosephosphate isomerase (TIM) structural topology [ 213 ].…”

Section: Klotho Proteinsmentioning

confidence: 99%

“…The mechanism involved in the inhibition of FGF23 production by insulin and insulin-like growth factor 1 (IGF1) was mediated through phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt)/ forkhead box protein O1 (FOXO1) signaling [ 67 ]. Interaction between FGF23 and KLA suggested that the C-terminus of FGF23 has two binding sites for KLA enabling a bivalent interaction [ 68 , 69 ]. Each of these binding sites was shown to bind to KLA on its own with a similar binding affinity [ 68 , 69 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interaction between FGF23 and KLA suggested that the C-terminus of FGF23 has two binding sites for KLA enabling a bivalent interaction [ 68 , 69 ]. Each of these binding sites was shown to bind to KLA on its own with a similar binding affinity [ 68 , 69 ]. Another recent study has demonstrated that inhibition of FGF23 signaling alleviates hypoferremia during acute inflammation [ 70 ].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The Saga of Endocrine FGFs

Phan

Saikia

Sonnaila

et al. 2021

Cells

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Fibroblast growth factors (FGFs) are cell-signaling proteins with diverse functions in cell development, repair, and metabolism. The human FGF family consists of 22 structurally related members, which can be classified into three separate groups based on their action of mechanisms, namely: intracrine, paracrine/autocrine, and endocrine FGF subfamilies. FGF19, FGF21, and FGF23 belong to the hormone-like/endocrine FGF subfamily. These endocrine FGFs are mainly associated with the regulation of cell metabolic activities such as homeostasis of lipids, glucose, energy, bile acids, and minerals (phosphate/active vitamin D). Endocrine FGFs function through a unique protein family called klotho. Two members of this family, α-klotho, or β-klotho, act as main cofactors which can scaffold to tether FGF19/21/23 to their receptor(s) (FGFRs) to form an active complex. There are ongoing studies pertaining to the structure and mechanism of these individual ternary complexes. These studies aim to provide potential insights into the physiological and pathophysiological roles and therapeutic strategies for metabolic diseases. Herein, we provide a comprehensive review of the history, structure–function relationship(s), downstream signaling, physiological roles, and future perspectives on endocrine FGFs.

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Section: Klotho Proteinssupporting

confidence: 80%

Section: Klotho Proteinsmentioning

confidence: 99%

Section: Klotho Proteinsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Saga of Endocrine FGFs

Phan

Saikia

Sonnaila

et al. 2021

Cells

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Branched Multimeric Peptides as Affinity Reagents for the Detection of α‐Klotho Protein

Zhang

Wang

et al. 2023

Angewandte Chemie

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α‐Klotho, an aging‐related protein found in the kidney, parathyroid gland, and choroid plexus, acts as an essential co‐receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. Decreased levels of α‐Klotho are a hallmark of age‐associated diseases. Detecting or labeling α‐Klotho in biological milieu has long been a challenge, however, hampering the understanding of its role. Here, we developed branched peptides by single‐shot parallel automated fast‐flow synthesis that recognize α‐Klotho with improved affinity relative to their monomeric versions. These peptides were further shown to selectively label Klotho for live imaging in kidney cells. Our results demonstrate that automated flow technology enables rapid synthesis of complex peptide architectures, showing promise for future detection of α‐Klotho in physiological settings.

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Branched Multimeric Peptides as Affinity Reagents for the Detection of α‐Klotho Protein

Zhang

Wang

et al. 2023

Angew Chem Int Ed

View full text Add to dashboard Cite

α-Klotho, an aging-related protein found in the kidney, parathyroid gland, and choroid plexus, acts as an essential co-receptor with the fibroblast growth factor 23 receptor complex to regulate serum phosphate and vitamin D levels. Decreased levels of α-Klotho are a hallmark of age-associated diseases. Detecting or labeling α-Klotho in biological milieu has long been a challenge, however, hampering the understanding of its role. Here, we developed branched peptides by singleshot parallel automated fast-flow synthesis that recognize α-Klotho with improved affinity relative to their monomeric versions. These peptides were further shown to selectively label Klotho for live imaging in kidney cells. Our results demonstrate that automated flow technology enables rapid synthesis of complex peptide architectures, showing promise for future detection of α-Klotho in physiological settings.

show abstract

Identification of a second Klotho interaction site in the C terminus of FGF23

Cited by 16 publications

References 34 publications

The Saga of Endocrine FGFs

The Saga of Endocrine FGFs

Branched Multimeric Peptides as Affinity Reagents for the Detection of α‐Klotho Protein

Branched Multimeric Peptides as Affinity Reagents for the Detection of α‐Klotho Protein

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