HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 36, 34226-34236, September 5, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/36/34226    most recent M303183200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Olsen, S. K. Articles by Mohammadi, M. Search for Related Content PubMed PubMed Citation Articles by Olsen, S. K. Articles by Mohammadi, M. Social Bookmarking                      What's this?

Fibroblast Growth Factor (FGF) Homologous Factors Share Structural but Not Functional Homology with FGFs^*

Shaun K. Olsen  , Meirav Garbi  ¶, Niccolo Zampieri , Anna V. Eliseenkova , David M. Ornitz ||, Mitchell Goldfarb ¶ **  and Moosa Mohammadi  ** 

From the Department of Pharmacology, New York University School of Medicine, New York, New York 10016, the ^¶Brookdale Department of Molecular, Cellular and Developmental Biology, Mount Sinai School of Medicine, New York, New York 10029, and the ^||Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110

Fibroblast growth factors (FGFs) interact with heparan sulfate glycosaminoglycans and the extracellular domains of FGF cell surface receptors (FGFRs) to trigger receptor activation and biological responses. FGF homologous factors (FHF1–FHF4; also known as FGF11–FGF14) are related to FGFs by substantial sequence homology, yet their only documented interactions are with an intracellular kinase scaffold protein, islet brain-2 (IB2) and with voltage-gated sodium channels. In this report, we show that recombinant FHFs can bind heparin with high affinity like classical FGFs yet fail to activate any of the seven principal FGFRs. Instead, we demonstrate that FHFs bind IB2 directly, furthering the contention that FHFs and FGFs elicit their biological effects by binding to different protein partners. To understand the molecular basis for this differential target binding specificity, we elucidated the crystal structure of FHF1b to 1.7-Å resolution. The FHF1b core domain assumes a -trefoil fold consisting of 12 antiparallel strands (₁ through ₁₂). The FHF1b -trefoil core is remarkably similar to that of classical FGFs and exhibits an FGF-characteristic heparin-binding surface as attested to by the number of bound sulfate ions. Using molecular modeling and structure-based mutational analysis, we identified two surface residues, Arg⁵² in the ₄–₅ loop and Val⁹⁵ in the ₉ strand of FHF1b that are required for the interaction of FHF1b with IB2. These two residues are unique to FHFs, and mutations of the corresponding residues of FGF1 to Arg and Val diminish the capacity of FGF1 to activate FGFRs, suggesting that these two FHF residues contribute to the inability of FHFs to activate FGFRs. Hence, FHFs and FGFs bear striking structural similarity but have diverged to direct related surfaces toward interaction with distinct protein targets.

Received for publication, March 27, 2003 , and in revised form, June 3, 2003.

The atomic coordinates and structure factors (code 1Q1U) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grants DE13686 (to M. M.), NS39906 (to M. G.), and CA60673 (to D. M. O). Beamline X4A at the National Synchrotron Light Source, a Department of Energy facility, is supported by the Howard Hughes Medical Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** Co-contributing senior authors.

To whom correspondence may be addressed. Tel.: 212-241-3394; Fax: 212-860-9279; E-mail: Mitchell.Goldfarb{at}mssm.edu.

To whom correspondence may be addressed. Tel.: 212-263-2907; Fax: 212-263-7133; E-mail: mohammad{at}saturn.med.nyu.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Goetz, K. Dover, F. Laezza, N. Shtraizent, X. Huang, D. Tchetchik, A. V. Eliseenkova, C.-F. Xu, T. A. Neubert, D. M. Ornitz, et al. Crystal Structure of a Fibroblast Growth Factor Homologous Factor (FHF) Defines a Conserved Surface on FHFs for Binding and Modulation of Voltage-gated Sodium Channels J. Biol. Chem., June 26, 2009; 284(26): 17883 - 17896. [Abstract] [Full Text] [PDF]

				M. S. Razzaque FGF23-mediated regulation of systemic phosphate homeostasis: is Klotho an essential player? Am J Physiol Renal Physiol, March 1, 2009; 296(3): F470 - F476. [Abstract] [Full Text] [PDF]

				F. Laezza, B. R. Gerber, J.-Y. Lou, M. A. Kozel, H. Hartman, A. Marie Craig, D. M. Ornitz, and J. M. Nerbonne The FGF14F145S Mutation Disrupts the Interaction of FGF14 with Voltage-Gated Na+ Channels and Impairs Neuronal Excitability J. Neurosci., October 31, 2007; 27(44): 12033 - 12044. [Abstract] [Full Text] [PDF]

				T. S. Lendvay, R. Sweet, C.-H. Han, T. Soygur, J.-F. Cheng, J. C. Plaire, J. S. Charleston, L. B. Charleston, S. Bagai, K. Cochrane, et al. Compensatory paracrine mechanisms that define the urothelial response to injury in partial bladder outlet obstruction Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1147 - F1156. [Abstract] [Full Text] [PDF]

				T. Raj, P. Kanellakis, G. Pomilio, G. Jennings, A. Bobik, and A. Agrotis Inhibition of Fibroblast Growth Factor Receptor Signaling Attenuates Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., August 1, 2006; 26(8): 1845 - 1851. [Abstract] [Full Text] [PDF]

				X. Zhang, O. A. Ibrahimi, S. K. Olsen, H. Umemori, M. Mohammadi, and D. M. Ornitz Receptor Specificity of the Fibroblast Growth Factor Family: THE COMPLETE MAMMALIAN FGF FAMILY J. Biol. Chem., June 9, 2006; 281(23): 15694 - 15700. [Abstract] [Full Text] [PDF]

				J.-Y. Lou, F. Laezza, B. R. Gerber, M. Xiao, K. A. Yamada, H. Hartmann, A. M. Craig, J. M. Nerbonne, and D. M. Ornitz Fibroblast growth factor 14 is an intracellular modulator of voltage-gated sodium channels J. Physiol., November 15, 2005; 569(1): 179 - 193. [Abstract] [Full Text] [PDF]

				C. Popovici, F. Conchonaud, D. Birnbaum, and R. Roubin Functional Phylogeny Relates LET-756 to Fibroblast Growth Factor 9 J. Biol. Chem., September 17, 2004; 279(38): 40146 - 40152. [Abstract] [Full Text] [PDF]

				E. K. Wittmack, A. M. Rush, M. J. Craner, M. Goldfarb, S. G. Waxman, and S. D. Dib-Hajj Fibroblast Growth Factor Homologous Factor 2B: Association with Nav1.6 and Selective Colocalization at Nodes of Ranvier of Dorsal Root Axons J. Neurosci., July 28, 2004; 24(30): 6765 - 6775. [Abstract] [Full Text] [PDF]

				O. A. Ibrahimi, F. Zhang, A. V. Eliseenkova, R. J. Linhardt, and M. Mohammadi Proline to arginine mutations in FGF receptors 1 and 3 result in Pfeiffer and Muenke craniosynostosis syndromes through enhancement of FGF binding affinity Hum. Mol. Genet., January 1, 2004; 13(1): 69 - 78. [Abstract] [Full Text] [PDF]