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Solution Structure of the Disulfide-Linked Dimer of Human Intestinal Trefoil Factor (TFF3):  The Intermolecular Orientation and Interactions Are Markedly Different from Those of Other Dimeric Trefoil Proteins

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MRC Biomedical NMR Centre, National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom, and Department of Pathology, Royal Victoria Infirmary, University of Newcastle, Newcastle, NE1 4LP, United Kingdom
Cite this: Biochemistry 2003, 42, 51, 15139–15147
Publication Date (Web):December 2, 2003
https://doi.org/10.1021/bi030182k
Copyright © 2003 American Chemical Society

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    Abstract

    The trefoil protein TFF3 forms a homodimer (via a disulfide linkage) that is thought to have increased biological activity over the monomer. The solution structure of the TFF3 dimer has been determined by NMR and compared with the structure of the TFF3 monomer and with other trefoil dimer structures (TFF1 and TFF2). The most significant structural differences between the trefoil domain in the monomer and dimer TFF3 are in the orientations of the N-terminal 310-helix (residues 10−12) and in the presence in the dimer of an additional 310-helix (residues 53−55) outside of the core region. The TFF3 dimer forms a more compact structure as compared with the TFF1 dimer where the two trefoil domains are connected by a flexible region with the monomer units being at variable distances from each other and in many different orientations. Although TFF2 is also a compact structure, the dispositions of its monomer units are very different from those of TFF3. The structural differences between the dimers result in the two putative receptor/ligand binding sites that remain solvent exposed in the dimeric structures having very different dispositions in the different dimers. Such differences have significant implications for the mechanism of action and functional specificity for the TFF class of proteins.

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     Funded by Cancer Research UK, the Wellcome Trust, and the Medical Research Council.

    *

     Corresponding authors. Telphone:  020 8959 3666. Fax:  020 8906 4477. E-mail:  (J.F.) [email protected]; (F.W.M.) fwm1@ leicester.ac.uk.

     National Institute for Medical Research.

    §

     University of Newcastle.

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    A 1H-15N HSQC spectrum and a table of interdomain NOEs. This material is available free of charge via the Internet at http://pubs.acs.org.

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