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Conserved domains on  [gi|224548987|ref|NP_001139118|]
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gamma-secretase subunit APH-1B isoform 2 [Homo sapiens]

Protein Classification

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
Aph-1 super family cl05572
Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase ...
 3-191 4.55e-57

Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase catalyzes the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. It is thought that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. Aph-1 and Pen-2, two membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Co-expression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity. APH-1 proteins have a similar but different set of motifs as compared to other families. Their four motifs are: QExxR, Fxxxx, Hxxxs and Hxxxs respectively. Given the inferred homology between APH-1 and other membrane proteases such as type II CAAX proteases and PrsW proteases, it is speculated that APH-1 may possess protease activity.


The actual alignment was detected with superfamily member pfam06105:

Pssm-ID: 461830  Cd Length: 224  Bit Score: 180.05  E-value: 4.55e-57
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987    3 AAVFFGCAFIAFGPALALYVFTIATEPLRIIFLIAGAFFWLVSLLISSLVWFMARVIIDNkdgptqkylLIFGAFVSVYI 82
Cdd:pfam06105   1 LAVFFGCTFIAFGPALALFVFTIAKDPLRIIILIASAFFWLVSLLLSSLLWFIVVPLKDT---------LAFGVVFSVLF 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987   83 QEMFRFAYYKLLKKASEGLKSINPGETAP-SMRLLAY-----------------------------------------AF 120
Cdd:pfam06105  72 QEAFRYLFYKLLKKAEEGLKAISEDGKSPiSKHQLAYvsglgfgvmsgafslvniladsfgpgtvglhgdspyffltsAF 151

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 224548987  121 MTLVIILLHVFWGIVFFDGCEKKKWGILLIVLLTHLLVSAQTFISSY--YGINLASAFIILVLMGTWAFLAAG 191
Cdd:pfam06105 152 ITLAFILLHTFWGVIFFDGCEKKNYWKIAFVVISHLLVSCLTLLNPAclYGASLLPIYLILVITGVWAFFVAG 224
 
Name Accession Description Interval E-value
Aph-1 pfam06105
Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase ...
 3-191 4.55e-57

Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase catalyzes the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. It is thought that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. Aph-1 and Pen-2, two membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Co-expression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity. APH-1 proteins have a similar but different set of motifs as compared to other families. Their four motifs are: QExxR, Fxxxx, Hxxxs and Hxxxs respectively. Given the inferred homology between APH-1 and other membrane proteases such as type II CAAX proteases and PrsW proteases, it is speculated that APH-1 may possess protease activity.


Pssm-ID: 461830  Cd Length: 224  Bit Score: 180.05  E-value: 4.55e-57
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987    3 AAVFFGCAFIAFGPALALYVFTIATEPLRIIFLIAGAFFWLVSLLISSLVWFMARVIIDNkdgptqkylLIFGAFVSVYI 82
Cdd:pfam06105   1 LAVFFGCTFIAFGPALALFVFTIAKDPLRIIILIASAFFWLVSLLLSSLLWFIVVPLKDT---------LAFGVVFSVLF 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987   83 QEMFRFAYYKLLKKASEGLKSINPGETAP-SMRLLAY-----------------------------------------AF 120
Cdd:pfam06105  72 QEAFRYLFYKLLKKAEEGLKAISEDGKSPiSKHQLAYvsglgfgvmsgafslvniladsfgpgtvglhgdspyffltsAF 151

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 224548987  121 MTLVIILLHVFWGIVFFDGCEKKKWGILLIVLLTHLLVSAQTFISSY--YGINLASAFIILVLMGTWAFLAAG 191
Cdd:pfam06105 152 ITLAFILLHTFWGVIFFDGCEKKNYWKIAFVVISHLLVSCLTLLNPAclYGASLLPIYLILVITGVWAFFVAG 224
 
Name Accession Description Interval E-value
Aph-1 pfam06105
Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase ...
 3-191 4.55e-57

Aph-1 protein; This family consists of several eukaryotic Aph-1 proteins.Gamma-secretase catalyzes the intramembrane proteolysis of Notch, beta-amyloid precursor protein, and other substrates as part of a new signaling paradigm and as a key step in the pathogenesis of Alzheimer's disease. It is thought that the presenilin heterodimer comprises the catalytic site and that a highly glycosylated form of nicastrin associates with it. Aph-1 and Pen-2, two membrane proteins genetically linked to gamma-secretase, associate directly with presenilin and nicastrin in the active protease complex. Co-expression of all four proteins leads to marked increases in presenilin heterodimers, full glycosylation of nicastrin, and enhanced gamma-secretase activity. APH-1 proteins have a similar but different set of motifs as compared to other families. Their four motifs are: QExxR, Fxxxx, Hxxxs and Hxxxs respectively. Given the inferred homology between APH-1 and other membrane proteases such as type II CAAX proteases and PrsW proteases, it is speculated that APH-1 may possess protease activity.


Pssm-ID: 461830  Cd Length: 224  Bit Score: 180.05  E-value: 4.55e-57
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987    3 AAVFFGCAFIAFGPALALYVFTIATEPLRIIFLIAGAFFWLVSLLISSLVWFMARVIIDNkdgptqkylLIFGAFVSVYI 82
Cdd:pfam06105   1 LAVFFGCTFIAFGPALALFVFTIAKDPLRIIILIASAFFWLVSLLLSSLLWFIVVPLKDT---------LAFGVVFSVLF 71

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 224548987   83 QEMFRFAYYKLLKKASEGLKSINPGETAP-SMRLLAY-----------------------------------------AF 120
Cdd:pfam06105  72 QEAFRYLFYKLLKKAEEGLKAISEDGKSPiSKHQLAYvsglgfgvmsgafslvniladsfgpgtvglhgdspyffltsAF 151

                         170       180       190       200       210       220       230
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|...
gi 224548987  121 MTLVIILLHVFWGIVFFDGCEKKKWGILLIVLLTHLLVSAQTFISSY--YGINLASAFIILVLMGTWAFLAAG 191
Cdd:pfam06105 152 ITLAFILLHTFWGVIFFDGCEKKNYWKIAFVVISHLLVSCLTLLNPAclYGASLLPIYLILVITGVWAFFVAG 224
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options: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.
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