nicastrin is an essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein)
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, ...
52-596
0e+00
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, nicastrin subfamily. Nicastrin is a main component of the gamma-secretase complex, which also contains presenilin, Pen-2 and Aph-1. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site. Dysfunction of gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1).
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Pssm-ID: 349877 [Multi-domain] Cd Length: 519 Bit Score: 615.97 E-value: 0e+00
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, ...
52-596
0e+00
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, nicastrin subfamily. Nicastrin is a main component of the gamma-secretase complex, which also contains presenilin, Pen-2 and Aph-1. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site. Dysfunction of gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1).
Pssm-ID: 349877 [Multi-domain] Cd Length: 519 Bit Score: 615.97 E-value: 0e+00
Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, ...
274-499
4.86e-97
Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). A region featured in this family has a fold similar to human transferrin receptor (TfR) and a bacterial aminopeptidase. It is implicated in the pathogenesis of Alzheimer's disease.
Pssm-ID: 310213 [Multi-domain] Cd Length: 227 Bit Score: 296.77 E-value: 4.86e-97
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
254-502
3.45e-08
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];
Pssm-ID: 441835 [Multi-domain] Cd Length: 257 Bit Score: 55.14 E-value: 3.45e-08
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, ...
52-596
0e+00
M28 Zn-peptidase nicastrin, a main component of gamma-secretase complex; Peptidase M28 family, nicastrin subfamily. Nicastrin is a main component of the gamma-secretase complex, which also contains presenilin, Pen-2 and Aph-1. Its extracellular domain sequence resembles aminopeptidases, but certain catalytic residues are not conserved. It is mainly localized to the endoplasmic reticulum and Golgi. It is highly glycosylated (Mr 120 kDa) and is essential for substrate recognition of the N-terminus of gamma-secretase substrates derived from APP and Notch. Nicastrin facilitates substrate cleavage by the catalytic presenilin subunit in the gamma-secretase complex. One conserved glutamate is especially important, probably because this residue forms an ion pair with the amino terminus of the substrate. This substrate-binding domain is often called the DAP domain (named after DYIGS, the amino acid stretch that modulates amyloid precursor protein (APP) processing, and Peptidase homologous region). The sequence of the substrate N-terminus is apparently not critical for the interaction, but a free amino group is. Thus, nicastrin can be considered a kind of gatekeeper for the gamma-secretase complex: type I membrane proteins that have not shed their ectodomains cannot interact properly with nicastrin and do not gain access to the active site. Dysfunction of gamma-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1).
Pssm-ID: 349877 [Multi-domain] Cd Length: 519 Bit Score: 615.97 E-value: 0e+00
Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, ...
274-499
4.86e-97
Nicastrin; Nicastrin and presenilin are two major components of the gamma-secretase complex, which executes the intramembrane proteolysis of type I integral membrane proteins such as the amyloid precursor protein (APP) and Notch. Nicastrin is synthesized in fibroblasts and neurons as an endoglycosidase-H-sensitive glycosylated precursor protein (immature nicastrin) and is then modified by complex glycosylation in the Golgi apparatus and by sialylation in the trans-Golgi network (mature nicastrin). A region featured in this family has a fold similar to human transferrin receptor (TfR) and a bacterial aminopeptidase. It is implicated in the pathogenesis of Alzheimer's disease.
Pssm-ID: 310213 [Multi-domain] Cd Length: 227 Bit Score: 296.77 E-value: 4.86e-97
Nicastrin small lobe; This domain is part of the protein Nicastrin, a component of gamma ...
49-223
4.46e-72
Nicastrin small lobe; This domain is part of the protein Nicastrin, a component of gamma secretase present in Homo sapiens. Gamma-secretase is thought to contribute to Alzheimer's disease development by generating beta-amyloid peptides. This domain is the known as the small lobe which forms the 'lid'. The lid is an extended surface loop that covers the hydrophilic pocket that is thought to be responsible for substrate recruitment. On substrate binding, the large lobe is thought to rotate relative to the small lobe.
Pssm-ID: 465690 Cd Length: 167 Bit Score: 229.82 E-value: 4.46e-72
M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also ...
254-501
1.76e-12
M28 Zn-peptidases include aminopeptidases and carboxypeptidases; Peptidase M28 family (also called aminopeptidase Y family) contains aminopeptidases as well as carboxypeptidases. They have co-catalytic zinc ions; each zinc ion is tetrahedrally co-ordinated, with three amino acid ligands plus activated water; one aspartate residue binds both metal ions. The aminopeptidases in this family are also called bacterial leucyl aminopeptidases, but are able to release a variety of N-terminal amino acids. IAP aminopeptidase and aminopeptidase Y preferentially release basic amino acids while glutamate carboxypeptidase II preferentially releases C-terminal glutamates. Plasma glutamate carboxypeptidase (PGCP) and glutamate carboxypeptidase II (NAALADase) hydrolyze dipeptides. Several members of the M28 peptidase family have PA domain inserts which may participate in substrate binding and/or in promoting conformational changes, which influence the stability and accessibility of the site to substrate. These include prostate-specific membrane antigen (PSMA), yeast aminopeptidase S (SGAP), human transferrin receptors (TfR1 and TfR2), plasma glutamate carboxypeptidase (PGCP) and several predicted aminopeptidases where relatively little is known about them. Also included in the M28 family are glutaminyl cyclases (QC), which are involved in N-terminal glutamine cyclization of many endocrine peptides. Nicastrin and nicalin belong to this family but lack the amino-acid conservation required for catalytically active aminopeptidases.
Pssm-ID: 349868 [Multi-domain] Cd Length: 202 Bit Score: 66.60 E-value: 1.76e-12
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein ...
254-502
3.45e-08
Zn-dependent amino- or carboxypeptidase, M28 family [Posttranslational modification, protein turnover, chaperones, Amino acid transport and metabolism];
Pssm-ID: 441835 [Multi-domain] Cd Length: 257 Bit Score: 55.14 E-value: 3.45e-08
Database: CDSEARCH/cdd Low complexity filter: no Composition Based Adjustment: yes E-value threshold: 0.01
References:
Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
of the residues that compose this conserved feature have been mapped to the query sequence.
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