Transglutaminase and Polyglutamine

Transglutaminase 2 can cross-link proteins and is implicated in many diseases, including cancer, celiac and Alzheimer’s. Polyglutamine stretches of amino acids in wheat gluten and human proteins can have lethal interactions with this ubiquitous enzyme.

I spend a lot of my time trying to fill in blanks or connect the dots -- I seek a grand conceptualization of the biological world. I want the molecular world to make sense to me. The problem is all of the loose ends and the task is to bring all of the loose ends together to make one beautiful whole. All of the components of the living world make sense, but they make sense only if the activities and interactions of most of the components are understood. Unfortunately, in many areas enough of the pieces are not understood, so the the whole can’t be envisioned. Let’s use an enzyme, transglutaminase 2, as an example.

Transglutaminase 2 (TG2) can replace the amino (-NH2) group at the end of a glutamine amino acid residue of a protein and attach its own sulfhydryl (-S-) in its place. Thus, the enzyme becomes covalently connected to another protein. Then, depending on what molecules crash into this conjugate, the protein can be transferred to the amino group of a lysine on second protein, to cross-link the two proteins, or a water molecule could interact to free the protein, but leaving a glutamic acid instead of the original glutamine. This explains the essence of the transglutaminase activity of the enzyme.

You can expect that I would have checked out the structure and amino acid sequence of TG2 and peeked at the literature on the enzyme. The enzyme has strong heparin-binding domains and those domains explain the ability to purify TG2 on heparin-sepharose, sticking of TG2 to the extracellular matrix (heparan sulfate proteoglycans), internalization and translocation into the nucleus.

TG2 can also cross-link proteins to toughen up the sloughed off layers of the skin and gut. It also can cross-link proteins in the cytoplasm as part of programmed cell death, with the result being protein aggregates that are easily endocytosed by phagocytic cells. TG2 in the nucleus can cross-link and stabilize histones.

TG2 can also be involved in pathology and where ever you see clumps of proteins in cells or tissues, TG2 should be suspected. TG2 is produced in close association with inflammation and the TG2 gene has an NFkB promoter, so TG2 is expressed along with other inflammatory genes.

Proteins cross-linked by TG2 are not readily degraded in cells. TG2 can of course reverse its cross-linking and separate proteins.

There are nine different diseases, including Huntington’s disease in which the protein products have long stretches of polyglutamines. Polyglutamines are excellent substrates for TG2 and proteins with long polyglutamine stretches are readily aggregated by TG2. Neurons suffering from this type of disease die stuffed with undigestable protein aggregates.

So what happens when you eat proteins with polyglutamines? The gluten proteins in wheat and other grains are these kinds of proteins. Most people digest grain proteins just fine, but an unlucky minority suffer when their intestinal TG2 attacks and gets cross-linked to the gluten proteins. The end result is production of antibodies to both the gluten proteins and to TG2, killing and scarring of the intestinal epithelium, and the symptoms of celiac (gluten intolerance). This may be an example of how plants have avoided being eaten. Insects and other herbivores must ingest polyglutamine-rich proteins in order to eat grains. These proteins destroy the gut of insects that are not adapted, because their TG enzymes are inactivated and aggregated. Most grain eating herbivores need a system to bypass the polyamines, but I don’t know what that is.

TG2 is also implicated in many cancers and I have invoked TG2 as the mechanism whereby glucosamine is anti-inflammatory. I have not touched on the role of TG2 as a signal molecule controlled by binding nucleotides, i.e. as a G protein, nor have a elaborated on all of its neurophysiological activities. Clearly TG2 is an enzyme with many activities and interactions, and it will be puzzling me for many years.