First Crystal Structure of Enzyme that Works Inside Membranes

The structure of an enzyme that has many regulatory functions and breaks peptide bonds of proteins where they pass through membranes within the cell has been described for the first time by Yale School of Medicine researchers in Nature.

The crystallized rhomboid structure, GlpG, provides the first detailed view of the intramembrane protease and correlates with earlier genetic and biochemical studies. Rhomboids are found in almost all organisms and, although little is known about their function in most species, they have been implicated in biological processes as diverse as mitochondrial function, invasion of host cells by parasites, bacterial communication, and, growth factor signaling.

The biochemical reaction of proteolysis within a membrane is very unusual. By definition, proteolysis involves water, but it is not clear where the water comes from in the oily membrane.

“Because there is seemingly no easy explanation, people always wonder if the protein factors involved are indeed proteases, and if mutations in them really affect proteolysis,” said the senior author, Ya Ha, assistant professor of pharmacology. “Our results suggest that the mechanism is real, which opens up more questions for the next phase of research.”

Intramembrane proteolysis has historical links to research on Alzheimer’s disease. The amyloid peptide deposits thought to be responsible for Alzheimer’s disease is derived from the large protein precursor, APP. The APP is chopped by two proteases and the resulting middle fragment is amyloid peptide.

“All known mutations that cause early-onset Alzheimer’s disease are mapped to three genes—APP, presenilin-1 and presenilin-2,” said Ha. “We now know that the presenilins are the intramembrane protease that chops up APP, converting it to amyloid peptide. Therefore, it is obvious that intramembrane proteolysis is really one of the centerpieces constituting what we now call the ‘amyloid hypothesis’ of Alzheimer’s disease.”

Co-authors at Yale include Yongcheng Wang and Yingjiu Zhang. The research was funded by the U.S. Department of Energy and the National Institutes of Health.

Nature: Published online October 11, 2006 doi:10.1038/nature05255