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

J. Biol. Chem., Vol. 281, Issue 28, 19578-19587, July 14, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/28/19578    most recent M601842200v1 Alert me when this article is cited 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pieren, M. Articles by Ballmer-Hofer, K. Search for Related Content PubMed PubMed Citation Articles by Pieren, M. Articles by Ballmer-Hofer, K. Social Bookmarking                      What's this?

Crystal Structure of the Orf Virus NZ2 Variant of Vascular Endothelial Growth Factor-E

IMPLICATIONS FOR RECEPTOR SPECIFICITY^*

Michel Pieren¹², Andrea E. Prota², Claudia Ruch³, Dirk Kostrewa, Armin Wagner^¶, Katrin Biedermann, Fritz K. Winkler, and Kurt Ballmer-Hofer⁴

From the Molecular Cell Biology and Structural Biology, Laboratory of Biomolecular Research, and the ^¶Swiss Light Source, Paul Scherrer Institut, 5232 Villigen, Switzerland

Mammalian vascular endothelial growth factors constitute a family of polypeptides, vascular endothelial growth factor (VEGF)-A, -B, -C, -D and placenta growth factor (PlGF), that regulate blood and lymphatic vessel development. VEGFs bind to three types of receptor tyrosine kinases, VEGF receptors 1, 2, and 3, that are predominantly expressed on endothelial and some hematopoietic cells. Pox viruses of the Orf family encode highly related proteins called VEGF-E that show only 25-35% amino acid identity with VEGF-A but bind with comparable affinity to VEGFR-2. The crystal structure of VEGF-E NZ2 described here reveals high similarity to the known structural homologs VEGF-A, PlGF, and the snake venoms Vammin and VR-1, which are all homodimers and contain the characteristic cysteine knot motif. Distinct conformational differences are observed in loop L1 and particularly in L3, which contains a highly flexible GS-rich motif that differs from all other structural homologs. Based on our structure, we created chimeric proteins by exchanging selected segments in L1 and L3 with the corresponding sequences from PlGF. Single loop mutants did not bind to either receptor, whereas a VEGF-E mutant in which both L1 and L3 were replaced gained affinity for VEGFR-1, illustrating the possibility to engineer receptor-specific chimeric VEGF molecules. In addition, changing arginine 46 to isoleucine in L1 significantly increased the affinity of VEGF-E for both VEGF receptors.

Received for publication, February 27, 2006 , and in revised form, April 17, 2006.

The atomic coordinates and structure factors (code 2GNN) 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 in part by Swiss National Foundation Grant 3100A0-100204 (to K. B.-H.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported by a fellowship from the Paul Scherrer Institut.

² Both contributed equally to this work.

³ Supported by Grant 3100AO-100204 from the Swiss National Science Foundation.

⁴ To whom correspondence should be addressed: Paul Scherrer Institut, Laboratory of Biomolecular Research, Molecular Cell Biology, 5232 Villigen-PSI, Switzerland. Tel.: 41-56-3104165; Fax: 41-56-3105288; E-mail: kurt.ballmer{at}psi.ch.

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

This article has been cited by other articles:

				S. Cebe-Suarez, F. S. Grunewald, R. Jaussi, X. Li, L. Claesson-Welsh, D. Spillmann, A. A. Mercer, A. E. Prota, and K. Ballmer-Hofer Orf virus VEGF-E NZ2 promotes paracellular NRP-1/VEGFR-2 coreceptor assembly via the peptide RPPR FASEB J, August 1, 2008; 22(8): 3078 - 3086. [Abstract] [Full Text] [PDF]

				M. K. Inder, N. Ueda, A. A. Mercer, S. B. Fleming, and L. M. Wise Bovine papular stomatitis virus encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2 J. Gen. Virol., March 1, 2007; 88(3): 781 - 791. [Abstract] [Full Text] [PDF]