Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity

Kuzina, Ekaterina S.; Ung, Peter Man-Un; Mohanty, Jyotidarsini; Tome, Francisco; Choi, Jungyuen; Pardon, Els; Steyaert, Jan; Lax, Irit; Schlessinger, Avner; Schlessinger, Joseph; Lee, Sangwon

doi:10.1073/pnas.1822055116

Title: Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity

Abstract

The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either α-Klotho or β-Klotho receptors. Structural analyses of ligandoccupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to β-Klotho or α-Klotho, respectively. They have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling. In this paper we describe the crystal structure the C-terminal tail of FGF19 (FGF19_CT) bound to sKLB and demonstrate that FGF19_CT and FGF21_CT bind to the same binding site on sKLB, via a multiturn D-P motif to site 1 and via a SP- S motif to the pseudoglycoside hydrolase region (site 2). Binding affinities to sKLB and cellular stimulatory activities of FGF19_CT, FGF21_CT, and a variety of chimeric mutants to cells expressing β-Klotho together with FGFR1c or FGFR4 were also analyzed. These experiments as well as detailed comparison of the structures of free and ligand-occupied sKLB to the structure of ligandoccupied sKLA reveal a general mechanism for recognition of endocrinemore »« less

Authors:

Kuzina, Ekaterina S. ^[1]; Ung, Peter Man-Un ^[2]; Mohanty, Jyotidarsini ^[1]; Tome, Francisco ^[1]; Choi, Jungyuen ^[1];

^[3]; Steyaert, Jan ^[3]; Lax, Irit ^[1]; Schlessinger, Avner ^[2]; Schlessinger, Joseph ^[1]; Lee, Sangwon ^[1]

Yale Univ. School of Medicine, New Haven, CT (United States)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Vrije Univ. Brussel, Brussels (Belgium)

Publication Date:: Wed Apr 03 00:00:00 EDT 2019

Research Org.:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Org.:: USDOE

OSTI Identifier:: 1558320

Grant/Contract Number:: GM124165; RR029205; OD021527; AC02-06CH11357

Resource Type:: Accepted Manuscript

Journal Name:: Proceedings of the National Academy of Sciences of the United States of America

Additional Journal Information:: Journal Volume: 116; Journal Issue: 16; Journal ID: ISSN 0027-8424

Publisher:: National Academy of Sciences

Country of Publication:: United States

Language:: ENGLISH

Subject:: 59 BASIC BIOLOGICAL SCIENCES; structural biology; cell signaling; endocrine FGF; phosphorylation; metabolism

Citation Formats


                    Kuzina, Ekaterina S., Ung, Peter Man-Un, Mohanty, Jyotidarsini, Tome, Francisco, Choi, Jungyuen, Pardon, Els, Steyaert, Jan, Lax, Irit, Schlessinger, Avner, Schlessinger, Joseph, and Lee, Sangwon. Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity.  United States: N. p., 2019. 
Web.  doi:10.1073/pnas.1822055116.

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                    Kuzina, Ekaterina S., Ung, Peter Man-Un, Mohanty, Jyotidarsini, Tome, Francisco, Choi, Jungyuen, Pardon, Els, Steyaert, Jan, Lax, Irit, Schlessinger, Avner, Schlessinger, Joseph, & Lee, Sangwon. Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity.  United States.  https://doi.org/10.1073/pnas.1822055116

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                    Kuzina, Ekaterina S., Ung, Peter Man-Un, Mohanty, Jyotidarsini, Tome, Francisco, Choi, Jungyuen, Pardon, Els, Steyaert, Jan, Lax, Irit, Schlessinger, Avner, Schlessinger, Joseph, and Lee, Sangwon. Wed .  
"Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity".  United States.  https://doi.org/10.1073/pnas.1822055116.  https://www.osti.gov/servlets/purl/1558320.

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@article{osti_1558320,

  title        = {Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity},

  author       = {Kuzina, Ekaterina S. and Ung, Peter Man-Un and Mohanty, Jyotidarsini and Tome, Francisco and Choi, Jungyuen and Pardon, Els and Steyaert, Jan and Lax, Irit and Schlessinger, Avner and Schlessinger, Joseph and Lee, Sangwon},

  abstractNote = {The three members of the endocrine fibroblast growth factor (FGF) family designated FGF19, FGF21, and FGF23 mediate their pleiotropic cellular effects by binding to and activating binary complexes composed of an FGF receptor (FGFR) bound to either α-Klotho or β-Klotho receptors. Structural analyses of ligandoccupied Klotho extracellular domains have provided important insights concerning mechanisms underlying the binding specificities of FGF21 and FGF23 to β-Klotho or α-Klotho, respectively. They have also demonstrated that Klotho proteins function as primary high-affinity receptors while FGFRs function as the catalytic subunits that mediate intracellular signaling. In this paper we describe the crystal structure the C-terminal tail of FGF19 (FGF19CT) bound to sKLB and demonstrate that FGF19CT and FGF21CT bind to the same binding site on sKLB, via a multiturn D-P motif to site 1 and via a SP- S motif to the pseudoglycoside hydrolase region (site 2). Binding affinities to sKLB and cellular stimulatory activities of FGF19CT, FGF21CT, and a variety of chimeric mutants to cells expressing β-Klotho together with FGFR1c or FGFR4 were also analyzed. These experiments as well as detailed comparison of the structures of free and ligand-occupied sKLB to the structure of ligandoccupied sKLA reveal a general mechanism for recognition of endocrine FGFs by Klotho proteins and regulatory interactions with FGFRs that control their pleiotropic cellular responses.},

  doi          = {10.1073/pnas.1822055116},

  journal      = {Proceedings of the National Academy of Sciences of the United States of America},

  number       = 16,

  volume       = 116,

  place        = {United States},

  year         = {Wed Apr 03 00:00:00 EDT 2019},

  month        = {Wed Apr 03 00:00:00 EDT 2019}

}

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Title: Structures of ligand-occupied β-Klotho complexes reveal a molecular mechanism underlying endocrine FGF specificity and activity

Abstract

Citation Formats

α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling journal, January 2018

Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling journal, January 2018

Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21 journal, January 2015

C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors journal, October 2008

Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands journal, March 2012

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation journal, December 2009

FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis journal, March 2011

Cellular signaling by fibroblast growth factor receptors journal, April 2005

Structures and mechanisms of glycosyl hydrolases journal, September 1995

Features and development of Coot journal, March 2010

Roles of FGF19 in Liver Metabolism journal, January 2011

Liver-specific Activities of FGF19 Require Klotho beta journal, July 2007

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

Regulation of Fibroblast Growth Factor-23 Signaling by Klotho journal, January 2006

Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo journal, May 2012

Klotho converts canonical FGF receptor into a specific receptor for FGF23 journal, October 2006

The DynDom database of protein domain motions journal, July 2003

FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho journal, April 2008

Different roles of N- and C- termini in the functional activity of FGF21 journal, May 2009

Understanding the Physiology of FGF21 journal, February 2016

betaKlotho is required for metabolic activity of fibroblast growth factor 21 journal, April 2007

XDS journal, January 2010

Stereochemistry and the Mechanism of Enzymatic Reactions journal, November 1953

Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation journal, December 1994

Phaser crystallographic software journal, July 2007

Molecular Mechanisms of Fibroblast Growth Factor Signaling in Physiology and Pathology journal, June 2013

The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis journal, November 2009

PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome journal, December 2019

Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation journal, February 2021

PHENIX: a comprehensive Python-based system for macromolecular structure solution. text, January 2010

Emerging concepts in pseudoenzyme classification, evolution, and signaling journal, August 2019

α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling
journal, January 2018

Structures of β-klotho reveal a ‘zip code’-like mechanism for endocrine FGF signalling
journal, January 2018

Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21
journal, January 2015

C-terminal Tail of FGF19 Determines Its Specificity toward Klotho Co-receptors
journal, October 2008

Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands
journal, March 2012

Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation
journal, December 2009

FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis
journal, March 2011

Cellular signaling by fibroblast growth factor receptors
journal, April 2005

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journal, September 1995

Features and development of Coot
journal, March 2010

Roles of FGF19 in Liver Metabolism
journal, January 2011

Liver-specific Activities of FGF19 Require Klotho beta
journal, July 2007

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

Regulation of Fibroblast Growth Factor-23 Signaling by Klotho
journal, January 2006

Fundamentals of FGF19 & FGF21 Action In Vitro and In Vivo
journal, May 2012

Klotho converts canonical FGF receptor into a specific receptor for FGF23
journal, October 2006

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FGF-21/FGF-21 receptor interaction and activation is determined by βKlotho
journal, April 2008

Different roles of N- and C- termini in the functional activity of FGF21
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Understanding the Physiology of FGF21
journal, February 2016

betaKlotho is required for metabolic activity of fibroblast growth factor 21
journal, April 2007

XDS
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journal, November 1953

Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation
journal, December 1994

Phaser crystallographic software
journal, July 2007

Molecular Mechanisms of Fibroblast Growth Factor Signaling in Physiology and Pathology
journal, June 2013

The FGF23–Klotho axis: endocrine regulation of phosphate homeostasis
journal, November 2009

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PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010

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journal, August 2019