Nicastrin the gatekeeper of gamma secretase

Once a year some hapless trucker from out of town gets stuck trying to drive under a nearby railroad bridge with a low clearance. This is exactly the function of nicastrin in the gamma secretase complex which produces the main component of the senile plaque, the aBeta peptide.

Gamma secretase is a 4 protein complex which functions as an enzyme which can cut the transmembrane segment of proteins embedded in the cell membrane. This was not understood for years, as cutting a protein here means hydrolyzing the amide bond of the protein, (e.g. adding water) and there is precious little water in the cell membrane which is nearly all lipid.

Big pharma has been attacking gamma secretase for years, as inhibiting it should stop production of the Abeta peptide and (hopefully) help Alzheimer’s disease. However the paper to be discussed [ Proc. Natl. Acad. Sci. vol. 113 p.n E509 – E518 ’16 ] notes that gamma secretase processes ‘scores’ of cell membrane proteins, so blanket inhibition might be dangerous.

The idea that Nicastrin is the gatekeeper for gamma secretase is at least a decade old [ Cell vol. 122 pp. 318 – 320 ’05 ], but back then people were looking for specific binding of nicastrin to gamma secretase targets.

The new paper provides a much simpler explanation. It won’t let any transmembrane segment of a protein near the active site of gamma secretase unless the extracellular part is lopped off. The answer is simple mechanics. Nicastrin is large (709 amino acids) but with just one transmembrane domain. Most of it is extracellular forming a blob extending out 25 Angstroms from the membrane, directly over the substrate binding pocket of gamma secretase. Only substrates with small portions outside the membrane (ectodomains) can pass through it. It’s the railroad bridge mentioned above. Take a look at the picture —

This is why a preliminary cleavage of the Amyloid Precursor Peptide (APP) is required for gamma secretase to work.

So all you had to do was write down the wavefunction for Nicastrin (all 709 amino acids) and solve it (assuming you even write it down) and you’d have the same answer — NOT. Only the totally macroscopic world explanation (railroad bridge) is of any use. What keeps proteins from moving through each other? Van der Waals forces. What help explain them. The Pauli exclusion principle, as pure quantum mechanics as it gets.

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