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Amyloid-beta Precursor Protein
Like Dr. Jekyll and Mr. Hyde, some seemingly innocent proteins have evil alter egos. The amyloid-beta precurson protein is an important example. It is a large membrane protein that normally plays an essential role in neural growth and repair. However, later in life, a corrupted form can destroy nerve cells, leading to the loss of thought and memory in Alzheimer's disease.
Anatomy of APP
Amyloid-beta precursor protein (APP) is a complicated protein with many functions. It is found on the surface of cells throughout the body. Like many membrane-tethered proteins, it is composed of several domains connected by flexible linkers, making it difficult to study as one intact piece. Looking to the PDB, we can find four pieces of APP, including three domains that extend on the outside of the cell (from top to bottom in blue, PDB entries 1mwp, 1owt, and 1rw6), and a special peptide that crosses the membrane (in green, from PDB entry 1iyt). There is also a small domain inside the cell, shown schematically here at the very bottom with a circle.
Bits and Pieces
APP plays roles both as an intact membrane protein, and when broken into pieces. It appears to play a central role in several processes, so it has been difficult to tease out all of the details and many of the functions of APP are still being discovered and studied. The intact protein is a receptor protein that sends signals through the G-protein system. It also binds to many structural molecules outside cells, such as heparin and laminin, so it may play a role in cell adhesion.
APP is also broken into several functional fragments by a set of dedicated proteases, termed secretases. These proteases cut on either side of the small peptide shown here in green. The large piece on top is then released outside the cell, where it helps control nerve growth, and the small piece at the bottom is released inside the cell, where it interacts with the protein-synthesis machinery in the nucleus. The little peptide remaining in the middle is the portion that has received the most study, since it is a central player in Alzheimer's disease.
Perilous Peptides
This little peptide is termed the amyloid-beta peptide, and it causes damage all out of proportion to its small size. In the full-length protein, it extends through the membrane, anchoring the protein. But as a free peptide, it leaves the membrane, changes shape and aggregates into long fibrils. These tough fibrils form dense plaques on nerve cells. The gradual accumulation of these plaques, along with the accumulation of a second protein inside nerve cells, leads to the onset of dementia as the brain slowly loses normal function.
Next: Clipping APP
Last changed by: A.Honegger,