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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.

    SOURCE: JBC.ORG


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    Seriously, what conclusion should we be expected to draw from the concluding sentence that: "To the team’s best knowledge, the disulfide bond switch in human TG2 represents the first example of a post-translational redox regulatory mechanism that is reversibly and allosterically modulated by two distinct proteins (ERp57 and TRX)"?

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    Translation to plain English that can be understood on some level by a layperson would be a start to making this article be anything other than a waste of my time to read.  As written, I gain zero insight.

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    Please write articles in plain English so the average non-scientist researcher can understand. If you want to write all the scientific stuff is fine but then translate so everyone can understand.

     

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    Lazy thinkers of America unite. Instead of pissing and mouning about not understanding the content, why don’t you express some gratitude for the scientific information that researchers are working hard, as reported, for trying to find help for Celiacs.

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    Great! Every discovery gets us one step closer. @AllenR the conclusion to draw from isn't what you quoted, but the last sentence; "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." 

    Edited by ptaps

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    If you think hard enough you can understand that they have found some type of protein or something and they are going to do more research to see what else they can find on this topic to help us celiacs. I have been waiting for the day to hear they found the solution. Even if there is no solution a vaccine or something would be nice.

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    I agree with Joanna, if you cannot understand something don't dismiss it. This finding is a breakthrough now we just have to wait for these results to appear in medication. 

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    It is exhausting enough just living a gluten free lifestyle.
    With the trivialization of the condition, the condescending
    attitude of many people, the social isolation, etc.etc.etc.,
    it would be really good to read articles that actually inform.
    Yes, yes, I'm grateful for the research but this article is
    laughably complex.

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    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?

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    That article IS plain English. If you have a high school degree and can't comprehend it, ask for your money back from your state board of ed.

    The article deals with medical details of a metabolic process. It was not written for a lay audience. Your local newspaper might pick it up, they target articles for a 6th grade education. (That's right, 6th grade for the average newspaper.) Or, you can ask your doctor to explain it to you. If you're not a molecular biology researcher...the simple translation is "Some guys found out some new stuff that might point towards why celiac can relapse and recur and maybe in twenty years it will lead to a way to turn it off and keep it off.

    That's what your newspaper will boil it down to, for a lay audience.

     

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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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