Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

Pair your accounts.

Export articles to Mendeley

Get article recommendations from ACS based on references in your Mendeley library.

You’ve supercharged your research process with ACS and Mendeley!

Click to create an ACS ID

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

Your Mendeley pairing has expired. Please reconnect
ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Figure 1Loading Img

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

View Author Information
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
Copyright © 2003 American Chemical Society

    Article Views





    Other access options
    Supporting Info (1)»


    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.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

     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@

     National Institute for Medical Research.


     University of Newcastle.

    Supporting Information Available

    Jump To

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

    Terms & Conditions

    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system:

    Cited By

    This article is cited by 40 publications.

    1. Vijay Pandey, Xi Zhang, Han-Ming Poh, Baocheng Wang, Dukanya Dukanya, Lan Ma, Zhinan Yin, Andreas Bender, Ganga Periyasamy, Tao Zhu, Kanchugarakoppal S. Rangappa, Basappa Basappa, Peter E. Lobie. Monomerization of Homodimeric Trefoil Factor 3 (TFF3) by an Aminonitrile Compound Inhibits TFF3-Dependent Cancer Cell Survival. ACS Pharmacology & Translational Science 2022, 5 (9) , 761-773.
    2. Nayara Braga Emidio, Rajeshwari Meli, Hue N. T. Tran, Hayeon Baik, Séverine Morisset-Lopez, Alysha G. Elliott, Mark A. T. Blaskovich, Sabrina Spiller, Annette G. Beck-Sickinger, Christina I. Schroeder, Markus Muttenthaler. Chemical Synthesis of TFF3 Reveals Novel Mechanistic Insights and a Gut-Stable Metabolite. Journal of Medicinal Chemistry 2021, 64 (13) , 9484-9495.
    3. Nayara Braga Emidio, Stuart M. Brierley, Christina I. Schroeder, Markus Muttenthaler. Structure, Function, and Therapeutic Potential of the Trefoil Factor Family in the Gastrointestinal Tract. ACS Pharmacology & Translational Science 2020, 3 (4) , 583-597.
    4. Timo K. Albert, Werner Laubinger, Stefan Müller, Franz-Georg Hanisch, Thomas Kalinski, Frank Meyer and Werner Hoffmann . Human Intestinal TFF3 Forms Disulfide-Linked Heteromers with the Mucus-Associated FCGBP Protein and Is Released by Hydrogen Sulfide. Journal of Proteome Research 2010, 9 (6) , 3108-3117.
    5. Deborah Fass, David J. Thornton. Mucin networks: Dynamic structural assemblies controlling mucus function. Current Opinion in Structural Biology 2023, 79 , 102524.
    6. Heather L. Rossi, Jorge F. Ortiz-Carpena, Devon Tucker, Andrew E. Vaughan, Nilam S. Mangalmurti, Noam A. Cohen, De’Broski R. Herbert. Trefoil Factor Family: A Troika for Lung Repair and Regeneration. American Journal of Respiratory Cell and Molecular Biology 2022, 66 (3) , 252-259.
    7. Feifei Cheng, Xuejuan Wang, Yi-Shiou Chiou, Chuyu He, Hui Guo, Yan Qin Tan, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E. Lobie. Trefoil factor 3 promotes pancreatic carcinoma progression via WNT pathway activation mediated by enhanced WNT ligand expression. Cell Death & Disease 2022, 13 (3)
    8. Yiqi Yang, Ziyang Lin, Quanyou Lin, Weijian Bei, Jiao Guo. Pathological and therapeutic roles of bioactive peptide trefoil factor 3 in diverse diseases: recent progress and perspective. Cell Death & Disease 2022, 13 (1)
    9. Lei Yang, Xiwei Zhang, Jiyin Zhang, Yuwei Liu, Tingting Ji, Jianing Mou, Xiaolian Fang, Shengcai Wang, Jun Chen. Low Expression of TFF3 in Papillary Thyroid Carcinoma may Correlate with Poor Prognosis but High Immune Cell Infiltration. Future Oncology 2022, 18 (3) , 333-348.
    10. Chen-Xing Zhang, Chu-Tian Wu, Lin Xiao, Shao-Hui Tang. The diagnostic and clinicopathological value of trefoil factor 3 in patients with gastric cancer: a systematic review and meta-analysis. Biomarkers 2021, 26 (2) , 95-102.
    11. Michael A. Järvå, James P. Lingford, Alan John, Niccolay Madiedo Soler, Nichollas E. Scott, Ethan D. Goddard-Borger. Trefoil factors share a lectin activity that defines their role in mucus. Nature Communications 2020, 11 (1)
    12. Nicole Maloney Belle, Yingbiao Ji, Karl Herbine, Yun Wei, JoonHyung Park, Kelly Zullo, Li-Yin Hung, Sriram Srivatsa, Tanner Young, Taylor Oniskey, Christopher Pastore, Wildaliz Nieves, Ma Somsouk, De’Broski R. Herbert. TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths. Nature Communications 2019, 10 (1)
    13. Marguerite Clyne, Felicity E. B. May. The Interaction of Helicobacter pylori with TFF1 and Its Role in Mediating the Tropism of the Bacteria Within the Stomach. International Journal of Molecular Sciences 2019, 20 (18) , 4400.
    14. A. V. Shestopalov, A. S. Dvornikov, O. V. Borisenko, A. V. Tutelyan. Trefoil factors — new markers of gastrointestinal mucosal barrier. Russian Journal of Infection and Immunity 2019, 9 (1) , 39-46.
    15. Vijay Pandey, Min Zhang, Mingliang You, Weijie Zhang, Rumei Chen, Wei Zhang, Lan Ma, Zheng-Sheng Wu, Tao Zhu, Xiu Qin Xu, Peter E. Lobie. Expression of two non-mutated genetic elements is sufficient to stimulate oncogenic transformation of human mammary epithelial cells. Cell Death & Disease 2018, 9 (12)
    16. Bastien Demouveaux, Valérie Gouyer, Frédéric Gottrand, Tetsuharu Narita, Jean-Luc Desseyn. Gel-forming mucin interactome drives mucus viscoelasticity. Advances in Colloid and Interface Science 2018, 252 , 69-82.
    17. Saichit Khummuang, Waraporn Phanphrom, Witida Laopajon, Watchara Kasinrerk, Ponlatham Chaiyarit, Supansa Pata. Production of Monoclonal Antibodies against Human Trefoil Factor 3 and Development of a Modified-Sandwich ELISA for Detection of Trefoil Factor 3 Homodimer in Saliva. Biological Procedures Online 2017, 19 (1)
    18. Shuo Diao, Qianqian Zheng, Jian Gao, Yiqun Yao, Siyang Ren, Yongjian Liu, Yinghui Xu. Trefoil factor 3 contributes to the malignancy of glioma via regulating HIF-1α. Oncotarget 2017, 8 (44) , 76770-76782.
    19. Eitaro Aihara, Kristen A. Engevik, Marshall H. Montrose. Trefoil Factor Peptides and Gastrointestinal Function. Annual Review of Physiology 2017, 79 (1) , 357-380.
    20. Philipp Arnold, Uta Rickert, Ann-Kristin Helmers, Jessica Spreu, Janna Schneppenheim, Ralph Lucius. Trefoil factor 3 shows anti-inflammatory effects on activated microglia. Cell and Tissue Research 2016, 365 (1) , 3-11.
    21. Niels‐Erik Viby, Lars Pedersen, Thomas Kromann Lund, Hannelouise Kissow, Vibeke Backer, Ebba Nexø, Lars Thim, Steen Seier Poulsen. Trefoil factor peptides in serum and sputum from subjects with asthma and COPD. The Clinical Respiratory Journal 2015, 9 (3) , 322-329.
    22. Felicity E B May, Bruce R Westley. TFF3 is a valuable predictive biomarker of endocrine response in metastatic breast cancer. Endocrine-Related Cancer 2015, 22 (3) , 465-479.
    23. Jianchun Gu, Leizhen Zheng, Li Zhang, Siyu Chen, Meiling Zhu, Xiaoping Li, Yajie Wang. TFF3 and HER2 expression and their correlation with survival in gastric cancer. Tumor Biology 2015, 36 (4) , 3001-3007.
    24. Niels-Erik Viby, Ebba Nexø, Hannelouise Kissow, Helle Andreassen, Paul Clementsen, Lars Thim, Steen Seier Poulsen. Trefoil factors (TFFs) are increased in bronchioalveolar lavage fluid from patients with chronic obstructive lung disease (COPD). Peptides 2015, 63 , 90-95.
    25. YONG LI, ZHENQING SUN, KEWEI LIU, WENSHENG QIU, RUYONG YAO, TONGTONG FENG, CHAO XIN, LU YUE. Prognostic significance of the co-expression of nucleophosmin and trefoil factor 3 in postoperative gastric cancer patients. Molecular and Clinical Oncology 2014, 2 (6) , 1055-1061.
    26. Jia-Rong Meng, Hui-Zhong Tang, Kai-Zong Zhou, Wu-Hong Shen, He-Yi Guo. TFF3 and survivin expressions associate with a lower survival rate in gastric cancer. Clinical and Experimental Medicine 2013, 13 (4) , 297-303.
    27. Jens Madsen, Grith Lykke Sorensen, Ole Nielsen, Ida Tornøe, Lars Thim, Claus Fenger, Jan Mollenhauer, Uffe Holmskov, . A Variant Form of the Human Deleted in Malignant Brain Tumor 1 (DMBT1) Gene Shows Increased Expression in Inflammatory Bowel Diseases and Interacts with Dimeric Trefoil Factor 3 (TFF3). PLoS ONE 2013, 8 (5) , e64441.
    28. Mie Hessellund Samson. Quantitative measurements of trefoil factor family peptides: possibilities and pitfalls. Scandinavian Journal of Clinical and Laboratory Investigation 2013, 73 (3) , 193-202.
    29. Ahmed R.H. Ahmed, Andrew B. Griffiths, Michael T. Tilby, Bruce R. Westley, Felicity E.B. May. TFF3 Is a Normal Breast Epithelial Protein and Is Associated with Differentiated Phenotype in Early Breast Cancer but Predisposes to Invasion and Metastasis in Advanced Disease. The American Journal of Pathology 2012, 180 (3) , 904-916.
    30. Gaofu Qi, Jingjing Li, Shengying Wang, Shanshan Xin, Peng Du, Qingye Zhang, Xiuyun Zhao. A chimeric peptide of intestinal trefoil factor containing cholesteryl ester transfer protein B cell epitope significantly inhibits atherosclerosis in rabbits after oral administration. Peptides 2011, 32 (4) , 790-796.
    31. Frederick W. Muskett, Samrat Thouta, Steven J. Thomson, Alexander Bowen, Phillip J. Stansfeld, John S. Mitcheson. Mechanistic Insight into Human ether-à-go-go-related Gene (hERG) K+ Channel Deactivation Gating from the Solution Structure of the EAG Domain. Journal of Biological Chemistry 2011, 286 (8) , 6184-6191.
    32. B.G. Campbell, M. Jabbes. Canine and feline trefoil factor family peptides: Highly conserved molecules with some unique characteristics. Research in Veterinary Science 2008, 85 (1) , 68-73.
    33. Patrick T. Fueger, Jonathan C. Schisler, Danhong Lu, Daniella A. Babu, Raghavendra G. Mirmira, Christopher B. Newgard, Hans E. Hohmeier. Trefoil Factor 3 Stimulates Human and Rodent Pancreatic Islet β-Cell Replication with Retention of Function. Molecular Endocrinology 2008, 22 (5) , 1251-1259.
    34. Motoko Sasaki, Hiroko Ikeda, Yasuni Nakanuma. Expression profiles of MUC mucins and trefoil factor family (TFF) peptides in the intrahepatic biliary system: Physiological distribution and pathological significance. Progress in Histochemistry and Cytochemistry 2007, 42 (2) , 61-110.
    35. Julie M. Kneller, Thomas Ehlen, Jasenka P. Matisic, Dianne Miller, Dirk Van Niekerk, Wan L. Lam, Marco Marra, Rebecca Richards-Kortum, Michelle Follen, Calum MacAulay, Steven J.M. Jones. Using LongSAGE to Detect Biomarkers of Cervical Cancer Potentially Amenable to Optical Contrast Agent Labelling. Biomarker Insights 2007, 2 , 117727190700200.
    36. Friedrich P. Paulsen, Monica S. Berry. Mucins and TFF peptides of the tear film and lacrimal apparatus. Progress in Histochemistry and Cytochemistry 2006, 41 (1) , 1-53.
    37. Jiri Kalabis, Ian Rosenberg, Daniel K. Podolsky. Vangl1 Protein Acts as a Downstream Effector of Intestinal Trefoil Factor (ITF)/TFF3 Signaling and Regulates Wound Healing of Intestinal Epithelium. Journal of Biological Chemistry 2006, 281 (10) , 6434-6441.
    38. WERNER HOFFMANN. TFF (Trefoil Factor Family) Peptides. 2006, 1147-1154.
    39. C. Emma Johns, Julia L. Newton, Bruce R. Westley, Felicity E. B. May. The Diurnal Rhythm of the Cytoprotective Human Trefoil Protein TFF2 Is Reduced by Factors Associated with Gastric Mucosal Damage: Ageing, Helicobacter pylori Infection, and Sleep Deprivation. The American Journal of Gastroenterology 2005, 100 (7) , 1491-1497.
    40. Steen Seier Poulsen, Hannelouise Kissow, Kristine Hare, Bolette Hartmann, Lars Thim. Luminal and parenteral TFF2 and TFF3 dimer and monomer in two models of experimental colitis in the rat. Regulatory Peptides 2005, 126 (3) , 163-171.