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The importance of Arg40 and 45 in the mitogenic activity and structural stability of basic fibroblast growth factor: Effects of acidic amino acid substitutions

Arakawa, Tsutomu and Holst, Paige and Narhi, Linda O. and Philo, John S. and Wen, Jie and Prestrelski, Steven J. and Zhu, Xiaotian and Rees, Douglas C. and Fox, Gary M. (1995) The importance of Arg40 and 45 in the mitogenic activity and structural stability of basic fibroblast growth factor: Effects of acidic amino acid substitutions. Journal of Protein Chemistry, 14 (5). pp. 263-274. ISSN 0277-8033. http://resolver.caltech.edu/CaltechAUTHORS:20150205-140649548

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Abstract

High-affinity binding of basic fibroblast growth factor (bFGF) to the tyrosine kinase receptor requires cell-surface heparan sulfate proteoglycan or exogenous addition of heparin. The crystal structure of bFGF shows Arg40 and 45 on the surface opposite to the heparin-binding region, suggesting that these charged residues may be involved in the receptor binding. Therefore, these amino acids were mutated to aspartic acid separately or simultaneously, and also a simultaneous mutation to glutamic acid was introduced. These mutants displayed a mitogenic activity decreased greater than tenfold compared to the wild-type protein. Addition of heparin had no effect on the activity, while these mutants showed heparin-binding characteristics resembling those of the native sequence protein. The mutants exhibited decreased stability compared to the native sequence protein. Gradual changes in conformation were observed by circular dichroic and infrared spectroscopy. Heparin chromatography also showed the presence of denatured form for these mutants. However, in the presence of multivalent anions such as citrate, sucrose octasulfate, and heparin, the conformation of the mutants resembled that of the wild-type protein, as revealed by X-ray crystallography and circular dichroism spectra of the mutant with a Arg40 → Asp substitution.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1007/BF01886783DOIArticle
http://link.springer.com/article/10.1007%2FBF01886783PublisherArticle
Contact Email Address:phoebe@caltech.edu
Additional Information:© 1995 Plenum Publishing Corporation. Received January 4, 1995.
Subject Keywords:bFGF; heparin; sucrose octasulfate
Record Number:CaltechAUTHORS:20150205-140649548
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20150205-140649548
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:54438
Collection:CaltechAUTHORS
Deposited By: SWORD User
Deposited On:08 Feb 2015 03:07
Last Modified:08 Feb 2015 03:07

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