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Conserved domains on  [gi|1720412916|ref|XP_030110206|]
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gamma-secretase-activating protein isoform X4 [Mus musculus]

Protein Classification

Graphical summary

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List of domain hits

 Name Accession Description Interval E-value
GSAP super family cl45535
gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, ...
 1-259 4.72e-104

gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, also called GSAP or PION, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein C-terminal fragment (APP-CTF). GSAP cleavage via caspase-3 is regulated and depends upon the availability of 5-lipoxygenase. Alzheimer's disease (AD), the most prevalent cause of dementia, is associated with accumulation of amyloid-beta peptide which is a major characteristic of the AD brain and responsible for some of its clinical manifestations. The anticancer drug imatinib had been shown to inhibit amyloid-beta formation without affecting Notch cleavage, by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.


The actual alignment was detected with superfamily member cd23105:

Pssm-ID: 438516  Cd Length: 514  Bit Score: 324.67  E-value: 4.72e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916   1 MFEMPLDITLTGLRFKLVNFGYDYRQDREKLCNQPSLCIFTNHTGSLCMCYSPKSDSREEITYSVFYLHKGYRKIFTAAP 80
Cdd:cd23105   246 MFELPLDIPLPNTRFTLVNFYYDIPLSNTIPDKSLNLCVLTSHGGSLCICYQHPLGSQESSTYSVFYNHKGETKTFTVSL 325

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916  81 GSADSQVTN----GADSQVTDGIAFLNLGYFVAVYSPGHFLHLLNIQHPDLVCHSLFLTGNN-------KIAAVLPPSPL 149
Cdd:cd23105   326 SHSGYLGHVirhlPKHSATRKRIFFTNLNYYVLVYLPGHFLHLLNVSHEDEPCHHILLHGKDvpwlstrPLLNACLTCPL 405

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 150 QSLPGSLVLDCYSGKVYRVTLDQSYLLRFLWNAHLDCERMAALHCILSCSQDPGfPEEQIIQWISEHVSACHSFDLIQEF 229
Cdd:cd23105   406 QSLSGSLLFDCCSGKLYKVSLNKDSLLELLWNCSLDSTRLALLHCVLVHLKDYQ-LEKKIIEWICQDIASLEVFDLLQEF 484

                         250       260       270
                  ....*....|....*....|....*....|
gi 1720412916 230 LIASSYWSVYAELDDMGMLLQYSSVLTWNT 259
Cdd:cd23105   485 LIASTYWAMRKQVDKDDLLLLPFTVTDTFR 514
GSAP-16 pfam14959
gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also ...
 404-511 6.25e-49

gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also known as PION, regulates gamma-secretase activity. The holo-protein is a large, approx 850 residue protein that is rapidly cleaved to an active 16 kDa C-terminal fragment that is the stable, predominant form. GSAP is expressed in inclusion bodies and is important in brain function. It dramatically and selectively increases neurotoxic beta-Amyloid production in the brain through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein C-terminal fragment (APP-CTF). Accumulation of neurotoxic beta-Amyloid is a major hallmark of Alzheimer's disease. Formation of beta-Amyloid is catalyzed by gamma-secretase, a protease with numerous substrates that catalyzes the intra-membrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). The secondary structure of GSAP is largely alpha-helical, lacking well-defined tertiary structure. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate.


:

Pssm-ID: 464405  Cd Length: 108  Bit Score: 165.87  E-value: 6.25e-49
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 404 LDLIWCLLETSWRKHSMHPLVLHLNSHCSAADFEVFHLMTRILDAASSLCLPLPPGFHSLHTILGVHCLPLYSLLHYIDN 483
Cdd:pfam14959   1 LELSRALCETVWRKAGLDPRLFLIDQLGSSQEWILFHLLERIYEAAEELAFPLPPGFHSLFTYLGYRCLPLHTFLQYIDH 80

                          90       100
                  ....*....|....*....|....*...
gi 1720412916 484 GVLLLTETAVTRLMKDLDNSEKNEQLKF 511
Cdd:pfam14959  81 GVFQLTEDFVKRLLKDLDDTEENEQLKF 108
 
Name Accession Description Interval E-value
GSAP cd23105
gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, ...
 1-259 4.72e-104

gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, also called GSAP or PION, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein C-terminal fragment (APP-CTF). GSAP cleavage via caspase-3 is regulated and depends upon the availability of 5-lipoxygenase. Alzheimer's disease (AD), the most prevalent cause of dementia, is associated with accumulation of amyloid-beta peptide which is a major characteristic of the AD brain and responsible for some of its clinical manifestations. The anticancer drug imatinib had been shown to inhibit amyloid-beta formation without affecting Notch cleavage, by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.


Pssm-ID: 438516  Cd Length: 514  Bit Score: 324.67  E-value: 4.72e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916   1 MFEMPLDITLTGLRFKLVNFGYDYRQDREKLCNQPSLCIFTNHTGSLCMCYSPKSDSREEITYSVFYLHKGYRKIFTAAP 80
Cdd:cd23105   246 MFELPLDIPLPNTRFTLVNFYYDIPLSNTIPDKSLNLCVLTSHGGSLCICYQHPLGSQESSTYSVFYNHKGETKTFTVSL 325

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916  81 GSADSQVTN----GADSQVTDGIAFLNLGYFVAVYSPGHFLHLLNIQHPDLVCHSLFLTGNN-------KIAAVLPPSPL 149
Cdd:cd23105   326 SHSGYLGHVirhlPKHSATRKRIFFTNLNYYVLVYLPGHFLHLLNVSHEDEPCHHILLHGKDvpwlstrPLLNACLTCPL 405

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 150 QSLPGSLVLDCYSGKVYRVTLDQSYLLRFLWNAHLDCERMAALHCILSCSQDPGfPEEQIIQWISEHVSACHSFDLIQEF 229
Cdd:cd23105   406 QSLSGSLLFDCCSGKLYKVSLNKDSLLELLWNCSLDSTRLALLHCVLVHLKDYQ-LEKKIIEWICQDIASLEVFDLLQEF 484

                         250       260       270
                  ....*....|....*....|....*....|
gi 1720412916 230 LIASSYWSVYAELDDMGMLLQYSSVLTWNT 259
Cdd:cd23105   485 LIASTYWAMRKQVDKDDLLLLPFTVTDTFR 514
GSAP-16 pfam14959
gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also ...
 404-511 6.25e-49

gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also known as PION, regulates gamma-secretase activity. The holo-protein is a large, approx 850 residue protein that is rapidly cleaved to an active 16 kDa C-terminal fragment that is the stable, predominant form. GSAP is expressed in inclusion bodies and is important in brain function. It dramatically and selectively increases neurotoxic beta-Amyloid production in the brain through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein C-terminal fragment (APP-CTF). Accumulation of neurotoxic beta-Amyloid is a major hallmark of Alzheimer's disease. Formation of beta-Amyloid is catalyzed by gamma-secretase, a protease with numerous substrates that catalyzes the intra-membrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). The secondary structure of GSAP is largely alpha-helical, lacking well-defined tertiary structure. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate.


Pssm-ID: 464405  Cd Length: 108  Bit Score: 165.87  E-value: 6.25e-49
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 404 LDLIWCLLETSWRKHSMHPLVLHLNSHCSAADFEVFHLMTRILDAASSLCLPLPPGFHSLHTILGVHCLPLYSLLHYIDN 483
Cdd:pfam14959   1 LELSRALCETVWRKAGLDPRLFLIDQLGSSQEWILFHLLERIYEAAEELAFPLPPGFHSLFTYLGYRCLPLHTFLQYIDH 80

                          90       100
                  ....*....|....*....|....*...
gi 1720412916 484 GVLLLTETAVTRLMKDLDNSEKNEQLKF 511
Cdd:pfam14959  81 GVFQLTEDFVKRLLKDLDDTEENEQLKF 108
 
Name Accession Description Interval E-value
GSAP cd23105
gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, ...
 1-259 4.72e-104

gamma-secretase-activating protein and similar proteins; Gamma-secretase activating protein, also called GSAP or PION, selectively increases amyloid-beta production through a mechanism involving its interaction with both gamma-secretase and its substrate, the amyloid-beta precursor protein C-terminal fragment (APP-CTF). GSAP cleavage via caspase-3 is regulated and depends upon the availability of 5-lipoxygenase. Alzheimer's disease (AD), the most prevalent cause of dementia, is associated with accumulation of amyloid-beta peptide which is a major characteristic of the AD brain and responsible for some of its clinical manifestations. The anticancer drug imatinib had been shown to inhibit amyloid-beta formation without affecting Notch cleavage, by preventing GSAP interaction with the gamma-secretase substrate, APP-CTF. Thus, GSAP can serve as an amyloid-beta-lowering therapeutic target without affecting other key functions of gamma-secretase.


Pssm-ID: 438516  Cd Length: 514  Bit Score: 324.67  E-value: 4.72e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916   1 MFEMPLDITLTGLRFKLVNFGYDYRQDREKLCNQPSLCIFTNHTGSLCMCYSPKSDSREEITYSVFYLHKGYRKIFTAAP 80
Cdd:cd23105   246 MFELPLDIPLPNTRFTLVNFYYDIPLSNTIPDKSLNLCVLTSHGGSLCICYQHPLGSQESSTYSVFYNHKGETKTFTVSL 325

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916  81 GSADSQVTN----GADSQVTDGIAFLNLGYFVAVYSPGHFLHLLNIQHPDLVCHSLFLTGNN-------KIAAVLPPSPL 149
Cdd:cd23105   326 SHSGYLGHVirhlPKHSATRKRIFFTNLNYYVLVYLPGHFLHLLNVSHEDEPCHHILLHGKDvpwlstrPLLNACLTCPL 405

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 150 QSLPGSLVLDCYSGKVYRVTLDQSYLLRFLWNAHLDCERMAALHCILSCSQDPGfPEEQIIQWISEHVSACHSFDLIQEF 229
Cdd:cd23105   406 QSLSGSLLFDCCSGKLYKVSLNKDSLLELLWNCSLDSTRLALLHCVLVHLKDYQ-LEKKIIEWICQDIASLEVFDLLQEF 484

                         250       260       270
                  ....*....|....*....|....*....|
gi 1720412916 230 LIASSYWSVYAELDDMGMLLQYSSVLTWNT 259
Cdd:cd23105   485 LIASTYWAMRKQVDKDDLLLLPFTVTDTFR 514
GSAP-16 pfam14959
gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also ...
 404-511 6.25e-49

gamma-Secretase-activating protein C-term; GSAP, or gamma-secretase-activating protein, also known as PION, regulates gamma-secretase activity. The holo-protein is a large, approx 850 residue protein that is rapidly cleaved to an active 16 kDa C-terminal fragment that is the stable, predominant form. GSAP is expressed in inclusion bodies and is important in brain function. It dramatically and selectively increases neurotoxic beta-Amyloid production in the brain through a mechanism involving its interactions with both gamma-secretase and its substrate, the amyloid precursor protein C-terminal fragment (APP-CTF). Accumulation of neurotoxic beta-Amyloid is a major hallmark of Alzheimer's disease. Formation of beta-Amyloid is catalyzed by gamma-secretase, a protease with numerous substrates that catalyzes the intra-membrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). The secondary structure of GSAP is largely alpha-helical, lacking well-defined tertiary structure. GSAP represents a type of gamma-secretase regulator that directs enzyme specificity by interacting with a specific substrate.


Pssm-ID: 464405  Cd Length: 108  Bit Score: 165.87  E-value: 6.25e-49
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1720412916 404 LDLIWCLLETSWRKHSMHPLVLHLNSHCSAADFEVFHLMTRILDAASSLCLPLPPGFHSLHTILGVHCLPLYSLLHYIDN 483
Cdd:pfam14959   1 LELSRALCETVWRKAGLDPRLFLIDQLGSSQEWILFHLLERIYEAAEELAFPLPPGFHSLFTYLGYRCLPLHTFLQYIDH 80

                          90       100
                  ....*....|....*....|....*...
gi 1720412916 484 GVLLLTETAVTRLMKDLDNSEKNEQLKF 511
Cdd:pfam14959  81 GVFQLTEDFVKRLLKDLDDTEENEQLKF 108
 
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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