|Fig. 1 from the minireview shows a schematic depiction of γ-secretase and SPP.
GxGD proteases are a family of intramembranous enzymes capable of hydrolyzing the transmembrane domain of some integral membrane proteins. The GxGD family is one of the three families of intramembrane-cleaving proteases discovered so far (along with the rhomboid and site-2 protease) and includes the γ-secretase and the signal peptide peptidase.
Although only recently discovered, a number of functions in human pathology and in numerous other biological processes have been attributed to γ-secretase and SPP. Taisuke Tomita and Takeshi Iwatsubo of the University of Tokyo highlighted the latest findings on the structure and function of γ-secretase and SPP in a recent minireview in The Journal of Biological Chemistry.
γ-secretase is involved in cleaving the amyloid-β precursor protein, thus producing amyloid-β peptide, the main component of senile plaques in Alzheimer’s disease patients’ brains. The complete structure of mammalian γ-secretase is not yet known; however, Tomita and Iwatsubo note that biochemical analyses have revealed it to be a multisubunit protein complex. Its catalytic subunit is presenilin, an aspartyl protease.
In vitro and in vivo functional and chemical biology analyses have revealed that presenilin is a modulator and mandatory component of the γ-secretase–mediated cleavage of APP. Genetic studies have identified three other components required for γ-secretase activity: nicastrin, anterior pharynx defective 1 and presenilin enhancer 2.
By coexpression of presenilin with the other three components, the authors managed to reconstitute γ-secretase activity. Using the substituted cysteine accessibility method, Tomita and Iwatsubo refined of topological analyses, which suggested the catalytic aspartates are located at the center of the nine transmembrane domains of presenilin, by revealing the exact location of the enzyme’s catalytic site. The minireview also describes in detail the formerly enigmatic mechanism of γ-secretase mediated cleavage.
SPP, an enzyme that cleaves remnant signal peptides in the membrane during the biogenesis of membrane proteins and signal peptides from major histocompatibility complex type I, also is involved in the maturation of proteins of the hepatitis C virus and GB virus B. Bioinformatics methods have revealed in fruit flies and mammals four SPP-like proteins, two of which are involved in immunological processes. By using γ-secretase inhibitors and modulators, it has been confirmed that SPP shares a similar GxGD active site and proteolytic activity with γ-secretase. Upon purification of the human SPP protein with the baculovirus/Sf9 cell system, single-particle analysis revealed further structural and functional details.
Dinu-Valentin Bălănescu (email@example.com) is a medical student at the Carol Davila University of Medicine and Pharmacy in Bucharest, Romania.