Molecular Mechanism of Inhibition of Nonclassical FGF-1 Export

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• 作者：Dakshinamurthy Rajalingam ; Thallapuranam Krishnaswamy S. Kumar ; Raffaella Soldi ; Irene Graziani ; Igor Prudovsky ; and Chin Yu
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：November 29, 2005
• 年：2005
• 卷：44
• 期：47
• 页码：15472 - 15479
• 全文大小：382K
• 年卷期：v.44,no.47(November 29, 2005)
• ISSN：1520-4995

文摘

Fibroblast growth factor (FGF-1) lacks a signal sequence and is exported by an unconventionalrelease mechanism. The nonclassical export of FGF-1 has been shown to be inhibited by an anti-allergicand anti-inflammatory drug, amlexanox (AMX). We investigate the molecular mechanism(s) underlyingthe inhibitory action of AMX on the release of FGF-1, using a variety of biophysical techniques includingmultidimensional NMR spectroscopy. AMX binds to FGF-1 and enhances its conformational stability.AMX binds to locations close to Cys30 and sterically blocks Cu²⁺-induced oxidation, leading to theformation of the homodimer of FGF-1. AMX-induced inhibition of the formation of the FGF-1 homodimeris observed both under cell-free conditions and in living cells. Results of this study suggest a novel approachfor the design of drugs against FGF-1-mediated disorders.