Human Trypsin IV is a 224 residue proteinase found in the brains of Alzheimer's patients (1). Trypsins are mainly found in the pancreas and aid in food digestion; however, there are other trypsins that are present in the human brain and are homologous to those found in other animals such as cows and mice (1). A lot of research is being conducted in this particular protein because of its association with neurodegenerative diseases.
Function
It is mostly associated with disease and abnormal function in the brain. It is unclear if there is a normal function of this protein, but there is research suggesting it plays a role in neural development (1).It is associated with neurodegenerative diseases such as Alzheimer's, and possibly dementia (2). Trypsin IV is found in glial cells and astrocytes (2). It breaks down proteins in the brain and forms aggregates called amyloids (2). These sticky structures harden and form plaque (2).
Progressive accumulation of plaque in the brain is what causes Alzheimer's. There are inhibitors of this protein present in the brain, but it is able to defend against them because it is too big to fit into the active site of the inhibitor (2). This protein is highly conserved, but in humans, there is a change in one of its residues, which is responsible for the immunity to its inhibitor. Gly193 has become Arginine in humans, and it can cause disease.
Disease
The disease it is most often associated with is Alzheimer's. The change from Gly193 to Arg193 disrupts normal brain activity. Arginine is much larger than Glycine, which causes steric hinderance in the active site of its inhibitor, APP (Amyloid Precursor Protein) trypsin inhibitor. Arginine is also positively charged which also interferes with the inhibitor. When APP Trypsin inhibitor cannot do its job, brain trypsin will start degrading other proteins in the brain and form amyloid (plaque). The plaque blocks nerve impulses. It starts in the hyppocampus, but will spread to other parts of the brain.
Relevance
This protein shows that trypsins are not limited to the pancreas, but its main relevance today is the fact that it is a primary cause of Alzheimer's. Research involving human trypsin IV is vital to the search for the disease which affects millions.
Structural highlights
