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  • Jefferson Adams
    Jefferson Adams

    Have Researchers Found the Off-Switch for a Key Celiac Protein?

    Reviewed and edited by a celiac disease expert.

      Does news that endoplasmic reticulum–resident protein 57 (ERp57) oxidatively inactivates human transglutaminase 2 mean that researchers have found the off-switch for a key celiac disease protein?

    Caption: Have researchers found a way to turn off a key celiac disease protein? Photo: CC--Marcin Wichary

    Celiac.com 03/13/2018 - Transglutaminase 2 (TG2) is a common intracellular and extracellular protein with multiple modes of post-translational regulation, including an allosteric disulfide bond between Cys-370–Cyss-371 that renders the enzyme inactive in the extracellular matrix. 

    Recent studies showed that extracellular TG2 is activated, or switched on, by the redox cofactor protein thioredoxin-1 (TRX), it is unclear how TG2 is switched off. 

    A team of researchers recently set out to answer that question. The research team includes Michael C. Yi, Arek V. Melkonian, James A. Ousey, and Chaitan Khosla. They are variously affiliated with the Departments of Chemical Engineering and Chemistry, School of Medicine, and Stanford ChEM-H at Stanford University in Stanford, California.

    Their team found that TG2 oxidation by small-molecule biological oxidants, including glutathione, cystine, and hydrogen peroxide, is likely not the inactivation trigger they are looking for. 

    They found the likely trigger to be endoplasmic reticulum (ER)–resident protein 57 (ERpp57), a protein in the ER that helps proteins inside a cell to fold.  ERp57 turns on TG2 from inside the cell.  ERp57 also inactivates TG2, but does so from outside the cell. Exactly how Erp57 moves to the outside of the cell, is still not understood.

    The research team found that ERp57 co-localizes with extracellular TG2 in cultured human umbilical vein endothelial cells (HUVECs). Moreover, ERp57 oxidized TG2 with a rate constant that was 400–2000-fold higher than seen in the smmall molecule oxidants. 

    Additionally, showed a significantly highr specificity for TG2 than those of other secreted redox proteins, including protein disulfide isomerase (PDI), ERp72, TRX, and quiescin sulfhydryl oxidase 1 (QSOX1). Lastly, siRNA-mediated ERp57 knockdown in HUVECs increased TG2-catalyzed transamidation in the extracellular environment. 

    To the teams best knowledge, the disulfide bond switch in human TG2 is the first such reversible regulatory trigger to be controlled by two distinct proteins, ERp57 and TRX.

    Getting a clear picture of how this process works, including how Erp57 moves from the inside to the cell to the outside of the cell, and how to turn it on and off at will, could help to fuel new treatments for celiac disease.


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    My challenge is with the title. It's totally misleading based on the information contained in the article. It set an expectation that wasn't met. And to clarify, it's with the Celiac.com title, not the author's title.

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    On 3/20/2018 at 5:24 AM, Guest Miss Cat said:

    I think its ugly to label someone a "lazy-American" because he/she doesnt understand Scientific terminology! Regardless of someone's nationality, physical capabilities or education level, we all have limitations to what we know, have learned & understand so let us begin here by being decent to those who have questions & want to understand better what is going on with celiac disease & trends & strides in attempting to improve the conditions of those who suffer from this disease! It's not at all an unfair request nor a lazy thing to ask that the scientific report be translated into simpler English so that all who suffer with the disease can understand the good news, whether he/she from Europe, North American, Central American, South American, Asian or & from any other continent on this planet! Let's be civil?

    So... if you don't understand something, ASK A QUESTION instead of being defensive of your lack of education. I don't understand every single nuance of these article either. But I can certainly pick up context clues. And if you ask COHERENT QUESTIONS, you'll generally find that intelligent people will respond with useful replies. 

    I say: Please keep challenging us to be better readers. And, also, please offer better summaries for the non-scientific reader.

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  • About Me

    Jefferson Adams is Celiac.com's senior writer and Digital Content Director. He earned his B.A. and M.F.A. at Arizona State University, and has authored more than 2,000 articles on celiac disease. His coursework includes studies in science, scientific methodology, biology, anatomy, medicine, logic, and advanced research. He previously served as SF Health News Examiner for Examiner.com, and devised health and medical content for Sharecare.com. Jefferson has spoken about celiac disease to the media, including an appearance on the KQED radio show Forum, and is the editor of the book "Cereal Killers" by Scott Adams and Ron Hoggan, Ed.D.

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