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J. Biol. Chem., Vol. 279, Issue 43, 45068-45075, October 22, 2004

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The Cysteine-rich Region of T1R3 Determines Responses to Intensely Sweet Proteins^*

Peihua Jiang, Qingzhou Ji, Zhan Liu, Lenore A. Snyder, Lumie M. J. Benard, Robert F. Margolskee¶, and Marianna Max||

From the Department of Physiology and Biophysics and Howard Hughes Medical Institute, Mount Sinai School of Medicine, New York, New York 10029

A wide variety of chemically diverse compounds taste sweet, including natural sugars such as glucose, fructose, sucrose, and sugar alcohols, small molecule artificial sweeteners such as saccharin and acesulfame K, and proteins such as monellin and thaumatin. Brazzein, like monellin and thaumatin, is a naturally occurring plant protein that humans, apes, and Old World monkeys perceive as tasting sweet but that is not perceived as sweet by other species including New World monkeys, mouse, and rat. It has been shown that heterologous expression of T1R2 plus T1R3 together yields a receptor responsive to many of the above-mentioned sweet tasting ligands. We have determined that the molecular basis for species-specific sensitivity to brazzein sweetness depends on a site within the cysteine-rich region of human T1R3. Other mutations in this region of T1R3 affected receptor activity toward monellin, and in some cases, overall efficacy to multiple sweet compounds, implicating this region as a previously unrecognized important determinant of sweet receptor function.

Received for publication, June 17, 2004 , and in revised form, August 4, 2004.

^* This work was supported by National Institutes of Health Grants T32DA007135-22 (to P. J.), DC003055 and DC003155 (to R. F. M.), and MH58811 (to M. M.) and National Science Foundation Grant 0115504 (to L. S.). 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 three supplemental figures.

^¶ Associate Investigator of Howard Hughes Medical Institute.

^|| To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Mount Sinai School of Medicine, Box 1677, 1425 Madison Ave., New York, NY 10029. Tel.: 212-659-8612; Fax: 212-849-2599; E-mail: max{at}inka.mssm.edu.

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