Insights into the molecular basis for fibroblast growth factor receptor autoinhibition and ligand-binding promiscuity

Proceedings of the National Academy of Sciences of the United States of America
Shaun K OlsenMoosa Mohammadi


The prototypical fibroblast growth factor receptor (FGFR) extracellular domain consists of three Ig domains (D1-D3) of which the two membrane-proximal D2 and D3 domains and the interconnecting D2-D3 linker bear the determinants of ligand binding and specificity. In contrast, D1 and the D1-D2 linker are thought to play autoinhibitory roles in FGFR regulation. Here, we report the crystal structure of the three-Ig form of FGFR3c in complex with FGF1, an FGF that binds promiscuously to each of the seven principal FGFRs. In this structure, D1 and the D1-D2 linker are completely disordered, demonstrating that these regions are dispensable for FGF binding. Real-time binding experiments using surface plasmon resonance show that relative to two-Ig form, the three-Ig form of FGFR3c exhibits lower affinity for both FGF1 and heparin. Importantly, we demonstrate that this autoinhibition is mediated by intramolecular interactions of D1 and the D1-D2 linker with the minimal FGF and heparin-binding D2-D3 region. As in the FGF1-FGFR2c structure, but not the FGF1-FGFR1c structure, the alternatively spliced betaC'-betaE loop is ordered and interacts with FGF1 in the FGF1-FGFR3c structure. However, in contrast to the FGF1-FGFR2c structure in which...Continue Reading


Sep 15, 2004·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Catherine Dodé, Jean-Pierre Hardelin
Mar 26, 2013·Acta Neuropathologica·Joan T Richtsmeier, Kevin Flaherty
Jul 4, 2012·Biomolecular NMR Assignments·Bettina ElshorstHarald Schwalbe
Jul 16, 2005·Analytical Biochemistry·Eva M MuñozRobert J Linhardt
Oct 24, 2013·The International Journal of Biochemistry & Cell Biology·Abbie E FearonRichard P Grose
May 3, 2005·Cytokine & Growth Factor Reviews·Lisa DaileyClaudio Basilico
Sep 8, 2011·Biochemistry·Fenghao Chen, Kalina Hristova
Aug 28, 2012·Journal of Chemical Information and Modeling·Ying WangJing-Fang Wang
May 29, 2008·Journal of Chemical Information and Modeling·Mala L Radhakrishnan, Bruce Tidor
Dec 18, 2012·Organic Letters·Steen U HansenJohn M Gardiner
Feb 14, 2013·Nature Reviews. Molecular Cell Biology·Regina Goetz, Moosa Mohammadi
Aug 22, 2009·The Journal of Biological Chemistry·Youli HuPierre-Marc Bouloux
Jul 14, 2010·The Journal of Biological Chemistry·Lijuan HeKalina Hristova
Jun 16, 2010·The Journal of Biological Chemistry·Krishna SaxenaHarald Schwalbe
Sep 8, 2012·The Journal of Biological Chemistry·Kirsten B BojesenVladimir Berezin
Apr 7, 2006·The Journal of Biological Chemistry·Xiuqin ZhangDavid M Ornitz
Jun 5, 2013·Cold Spring Harbor Perspectives in Biology·Artur A Belov, Moosa Mohammadi
Feb 14, 2013·Science Signaling·Malgorzata ZakrzewskaAntoni Wiedlocha
Mar 28, 2012·Molecular and Cellular Biology·Regina GoetzMoosa Mohammadi
Aug 18, 2012·Advances in Urology·Erica di MartinoMargaret A Knowles
Apr 22, 2009·The Journal of Clinical Investigation·Jing QingAvi Ashkenazi
May 16, 2012·The Journal of Clinical Investigation·Yingli WangEthylin Wang Jabs
Feb 24, 2010·BMC Developmental Biology·Yingli WangEthylin Wang Jabs
Sep 15, 2009·BMC Evolutionary Biology·Alfred L RocaAlex D Greenwood
Jun 21, 2011·Orphanet Journal of Rare Diseases·Eeva-Maria LaitinenTaneli Raivio
Aug 11, 2011·PloS One·Katarina BlagovicJoel Voldman
Mar 16, 2007·Proceedings of the National Academy of Sciences of the United States of America·Bridget M RileyJeffrey C Murray
Apr 15, 2014·Protein Expression and Purification·Aleksandra Sokolowska-WedzinaJacek Otlewski
Sep 28, 2014·Molecular and Cellular Endocrinology·S B WingeE Rajpert-De Meyts
Mar 28, 2008·Neurochemical Research·Vladislav V Kiselyov
Apr 23, 2008·Neurochemical Research·Stine Maria HansenVladimir Berezin
Apr 16, 2014·Journal of Cellular Physiology·Siew-Ging Gong
Sep 8, 2010·Science China. Life Sciences·GuiPing RenDeShan Li
Jan 5, 2016·Nature Communications·Sarvenaz Sarabipour, Kalina Hristova


Jan 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·T MikiStuart A Aaronson
Apr 15, 1991·Proceedings of the National Academy of Sciences of the United States of America·A E ErikssonB W Matthews
Mar 1, 1991·Acta Crystallographica. Section A, Foundations of Crystallography·T A JonesM Kjeldgaard
Jan 1, 1993·Advances in Cancer Research·D E Johnson, L T Williams
Jun 21, 1996·The Journal of Biological Chemistry·David M OrnitzMitchell Goldfarb
Jan 15, 1998·Progress in Nucleic Acid Research and Molecular Biology·W L McKeehanM Kan
Oct 3, 1998·Acta Crystallographica. Section D, Biological Crystallography·A T BrüngerG L Warren
Sep 18, 1999·Cell·A N PlotnikovMoosa Mohammadi
Jan 5, 2000·Proceedings of the National Academy of Sciences of the United States of America·D J StauberW A Hendrickson
Feb 20, 2003·Proceedings of the National Academy of Sciences of the United States of America·Brian K YehMoosa Mohammadi
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

Related Concepts

Ligand Binding
Magnetic Resonance Imaging
Trefoil (plant)
CLIP1 gene
Splice Variants, Protein
Trefoil Motif
Fibroblast Growth Factor Receptors

Trending Feeds


Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Sexual Dimorphism in Neurodegeneration

There exist sex differences in neurodevelopmental and neurodegenerative disorders. For instance, multiple sclerosis is more common in women, whereas Parkinson’s disease is more common in men. Here is the latest research on sexual dimorphism in neurodegeneration

HLA Genetic Variation

HLA genetic variation has been found to confer risk for a wide variety of diseases. Identifying these associations and understanding their molecular mechanisms is ongoing and holds promise for the development of therapeutics. Find the latest research on HLA genetic variation here.

Super-resolution Microscopy

Super-resolution microscopy is the term commonly given to fluorescence microscopy techniques with resolutions that are not limited by the diffraction of light. Here are the latest discoveries pertaining to super-resolution microscopy.

Genetic Screens in iPSC-derived Brain Cells

Genetic screening is a critical tool that can be employed to define and understand gene function and interaction. This feed focuses on genetic screens conducted using induced pluripotent stem cell (iPSC)-derived brain cells.

Brain Lower Grade Glioma

Low grade gliomas in the brain form from oligodendrocytes and astrocytes and are the slowest-growing glioma in adults. Discover the latest research on these brain tumors here.

CD4/CD8 Signaling

Cluster of differentiation 4 and 8 (CD8 and CD8) are glycoproteins founds on the surface of immune cells. Here is the latest research on their role in cell signaling pathways.

Alignment-free Sequence Analysis Tools

Alignment-free sequence analyses have been applied to problems ranging from whole-genome phylogeny to the classification of protein families, identification of horizontally transferred genes, and detection of recombined sequences. Here is the latest research.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Related Papers

Protein Science : a Publication of the Protein Society
Vladislav V KiselyovFlemming M Poulsen
Proceedings of the National Academy of Sciences of the United States of America
Brian K YehMoosa Mohammadi
Protein Science : a Publication of the Protein Society
Vladislav V KiselyovVladimir Berezin
© 2020 Meta ULC. All rights reserved