InterPro domain: IPR042524

Presenilins are polytopic transmembrane (TM) proteins, mutations in whichare associated with the occurrence of early-onset familial Alzheimer'sdisease, a rare form of the disease that results from a single-genemutation [ 1 , 2 ]. Alzheimer's disease is associated with the formation of extracellular deposits of amyloid, which contain aggregates of the amyloid-beta peptide. The beta-peptides are released from the Alzheimer's amyloid precursor protein (APP) by the action of two peptidase activities: "beta-secretase" cleaves at the N terminus of the peptide, and "gamma-secretase" cleaves at the C terminus. The gamma-secretase cleavage occurs in a transmembrane segment of APP. Presenilin, which exists in a complex with nicastrin, APH-1 and PEN-2, has been identified as gamma-secretase from its deficiency [ 3 ] and mutation of its active site residues [ 4 ], but proteolytic activity has only been directly demonstrated on a peptide derived from APP [ 5 ].

Presenilin-1 is also known to process notch proteins [ 5 ] and syndecan-3 [ 6 ].

Presenilin has nine transmembrane regions with the active site aspartic acid residues located on TM6, within a Tyr-Asp motif, and TM7, within a Gly-Xaa-Gly-Asp motif [ 7 ]. The protein autoprocesses to form an amino-terminal fragment (TMs 1-6) and a C-terminal fragment (TMs 7-9) [ 7 ]. The tertiary structure of the human gamma-sectretase complex has been solved [ 8 ]. Nicastrin is extracellular, whereas presenilin-1, APH-1 and PEN-2 are all transmembrane proteins. The transmembrane regions of all three proteins form a horseshoe shape.

This superfamily represents the C-terminal region of aspartic peptidases belonging to the MEROPS peptidase family A22 (presenilin family), subfamily A22A, the type example being presenilin 1 from Homo sapiens (Human).

1. Introduction: genetic determinants of mid- and late-life dementias. Cell. Mol. Life Sci. 54, 895-6
2. Presenilin mutations in Alzheimer's disease. Hum. Mutat. 11, 183-90
3. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature 391, 387-90
4. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature 398, 513-7
5. Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis. J. Biol. Chem. 276, 40268-73
6. Syndecan 3 intramembrane proteolysis is presenilin/gamma-secretase-dependent and modulates cytosolic signaling. J. Biol. Chem. 278, 48651-7
7. Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 17, 181-90
8. An atomic structure of human γ-secretase. Nature 525, 212-7