Gamma secretase
Gamma-secretase (Nicastrin subunit) | |||||||||
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cryo-electron microscopy.[1] | |||||||||
Identifiers | |||||||||
Symbol | Gamma-secretase, γ-secretase | ||||||||
Pfam | PF05450 | ||||||||
InterPro | IPR008710 | ||||||||
OPM superfamily | 244 | ||||||||
OPM protein | [ 5fn5[ | ||||||||
Membranome | 155 | ||||||||
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Gamma secretase is a multi-subunit
Subunits and assembly
The gamma secretase complex consists of four individual proteins:
aspartyl protease, is the catalytic subunit; mutations in the presenilin gene have been shown to be a major genetic risk factor for Alzheimer's disease [12] and modulates immune cell activity.[13] In humans, two forms of presenilin and two forms of APH-1 have been identified in the genome; one of the APH homologs can also be expressed in two isoforms via alternative splicing, leading to at least six different possible gamma secretase complexes that may have tissue- or cell type specificity.[14]
The proteins in the gamma secretase complex are heavily modified by
conserved alpha helix interaction motif and aids in initiating assembly of premature components.[18]
Recent research has shown that interaction of the gamma secretase complex with the
β-amyloid.[19]
Cellular trafficking
The gamma secretase complex is thought to assemble and mature via proteolysis in the early
Function
Gamma secretase is an internal protease that cleaves within the membrane-spanning domain of its
cryo-electron microscopy single-particle analysis at 4.5 angstrom resolution[25] and in 2015 an atomic-resolution (3.4 angstrom) cryo-EM structure was reported.[1]
The gamma secretase complex is unusual among proteases in having a "sloppy" cleavage site at the C-terminal site in
familial Alzheimer's disease.[26] Although older data suggested that different forms of the gamma secretase complex could be differentially responsible for generating different amyloid beta isoforms,[27] current evidence indicates that the C-terminus of amyloid beta is produced by a series of single-residue cleavages by the same gamma secretase complex.[28][29][30] Earlier cleavage sites produce peptides of length 46 (zeta-cleavage) and 49 (epsilon-cleavage).[29]
See also
- DAPT (chemical), a γ-secretase inhibitor
References
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