Target type: biologicalprocess
The proteolytic cleavage of a transmembrane protein leading to the release of an intracellular domain. [PMID:12808018]
Membrane protein intracellular domain proteolysis is a critical regulatory mechanism that controls the fate and function of transmembrane proteins. It involves the cleavage of the intracellular domain (ICD), the portion of the protein located within the cytoplasm, by specific proteases. This process can trigger a cascade of intracellular signaling events, leading to diverse cellular responses.
The proteolytic cleavage of the ICD can occur at different sites within the protein, generating distinct fragments with unique signaling properties. The specific protease involved in the cleavage is often determined by the type of membrane protein and the cellular context.
Here's a detailed breakdown of the process:
1. **Targeting and Recognition:** The initial step involves the recognition and targeting of the membrane protein by a specific protease. This recognition can be mediated by protein-protein interactions, post-translational modifications, or specific motifs within the ICD.
2. **Proteolytic Cleavage:** The protease then cleaves the ICD at a specific site, releasing the intracellular domain from the membrane. This cleavage can be either constitutive or regulated, depending on the specific protein and cellular signals.
3. **ICD Translocation:** In some cases, the cleaved ICD can translocate to the nucleus, where it can interact with transcription factors and alter gene expression. This translocation can be facilitated by nuclear localization signals within the ICD.
4. **Signaling Cascade:** The cleaved ICD can activate various signaling pathways, including those involving kinases, phosphatases, and second messengers. This activation can lead to changes in cell growth, differentiation, survival, and other cellular processes.
5. **Protein Degradation:** The cleaved ICD can also be targeted for degradation by proteasomes or other cellular machinery, contributing to the regulation of protein levels.
The proteolytic cleavage of membrane protein ICDs plays a crucial role in a wide range of biological processes, including:
- **Signal transduction:** Mediating communication between the extracellular environment and the intracellular signaling pathways.
- **Cell fate determination:** Regulating cell growth, differentiation, and survival.
- **Immune response:** Controlling the activation and function of immune cells.
- **Development:** Regulating the formation and differentiation of tissues and organs.
Understanding the mechanisms of membrane protein ICD proteolysis is essential for deciphering the complex regulatory networks that govern cell function and human health. Aberrant proteolysis can contribute to various diseases, including cancer and neurodegenerative disorders. Therefore, targeting this process holds great promise for developing novel therapeutic strategies.'
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Protein | Definition | Taxonomy |
---|---|---|
Gamma-secretase subunit PEN-2 | A gamma-secretase subunit PEN-2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9NZ42] | Homo sapiens (human) |
Gamma-secretase subunit APH-1A | A gamma-secretase subunit APH-1A that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q96BI3] | Homo sapiens (human) |
Nicastrin | A nicastrin that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q92542] | Homo sapiens (human) |
Gamma-secretase subunit APH-1B | A gamma-secretase subunit APH-1B that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8WW43] | Homo sapiens (human) |
Signal peptide peptidase-like 2A | A signal peptide peptidase-like 2A that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8TCT8] | Homo sapiens (human) |
Membrane-bound transcription factor site-1 protease | A membrane-bound transcription factor site-1 protease that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q14703] | Homo sapiens (human) |
Disintegrin and metalloproteinase domain-containing protein 9 | A disintegrin and metalloproteinase domain-containing protein 9 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q13443] | Homo sapiens (human) |
Matrilysin | A matrilysin that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09237] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
2,3-dihydroxybenzoic acid | 2,3-dihydroxybenzoic acid : A dihydroxybenzoic acid that is benzoic acid substituted by hydroxy groups at positions 2 and 3. It occurs naturally in Phyllanthus acidus and in the aquatic fern Salvinia molesta. 2,3-dihydroxybenzoic acid: RN given refers to parent cpd dihydroxybenzoic acid : Any member of the class of hydroxybenzoic acids carrying two phenolic hydroxy groups on the benzene ring and its derivatives. | dihydroxybenzoic acid | human xenobiotic metabolite; plant metabolite |
protocatechuic acid | 3,4-dihydroxybenzoic acid : A dihydroxybenzoic acid in which the hydroxy groups are located at positions 3 and 4. protocatechuic acid: RN given refers to parent cpd; structure | catechols; dihydroxybenzoic acid | antineoplastic agent; EC 1.1.1.25 (shikimate dehydrogenase) inhibitor; EC 1.14.11.2 (procollagen-proline dioxygenase) inhibitor; human xenobiotic metabolite; plant metabolite |
gallic acid | gallate : A trihydroxybenzoate that is the conjugate base of gallic acid. | trihydroxybenzoic acid | antineoplastic agent; antioxidant; apoptosis inducer; astringent; cyclooxygenase 2 inhibitor; EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor; geroprotector; human xenobiotic metabolite; plant metabolite |
beta-resorcylic acid | beta-resorcylic acid: RN given refers to parent cpd; structure | ||
2,5-dihydroxybenzoic acid | 2,5-dihydroxybenzoic acid : A dihydroxybenzoic acid having the two hydroxy groups at the 2- and 5-positions. 2,5-dihydroxybenzoic acid: RN given refers to parent cpd; a oxidative product of saligenin | dihydroxybenzoic acid | EC 1.13.11.33 (arachidonate 15-lipoxygenase) inhibitor; fungal metabolite; human metabolite; MALDI matrix material; mouse metabolite |
7-amino-4-chloro-3-methoxy-2-benzopyran-1-one | isocoumarins | ||
veratric acid | 3,4-dimethoxybenzoic acid : A member of the class of benzoic acids that is benzoic acid substituted by methoxy groups at positions 2 and 3. veratric acid: RN given refers to parent cpd; structure | benzoic acids | allergen; plant metabolite |
methyl gallate | methyl 3,4,5-trihydroxybenzoate : A gallate ester obtained by the formal condensation of gallic acid with methanol. It exhibits anti-oxidant, anti-tumor, anti-microbial and anti-inflammatory properties. methyl gallate: has both immunosuppressive and phytogenic antineoplastic activities; isolated from Acer saccharinum | gallate ester | anti-inflammatory agent; antioxidant; plant metabolite |
3,4,5-trimethoxybenzoic acid | 3,4,5-trimethoxybenzoic acid : A benzoic acid derivative carrying 3-, 4- and 5-methoxy substituents. 3,4,5-trimethoxybenzoic acid: RN given refers to parent cpd; structure | benzoic acids; methoxybenzenes | human urinary metabolite; human xenobiotic metabolite; plant metabolite |
syringic acid | syringic acid : A dimethoxybenzene that is 3,5-dimethyl ether derivative of gallic acid. syringic acid: RN given refers to parent cpd; structure in third source | benzoic acids; dimethoxybenzene; phenols | plant metabolite |
epigallocatechin gallate | (-)-epigallocatechin 3-gallate : A gallate ester obtained by the formal condensation of gallic acid with the (3R)-hydroxy group of (-)-epigallocatechin. epigallocatechin gallate: a steroid 5alpha-reductase inhibitor and antimutagen in green tea (Camellia sinensis) | flavans; gallate ester; polyphenol | antineoplastic agent; antioxidant; apoptosis inducer; geroprotector; Hsp90 inhibitor; neuroprotective agent; plant metabolite |
tarenflurbil | tarenflurbil: R-enantiomer of flurbiprofen but not a COX inhibitor; modulates NF-kB, gamma-secretase, amyloid beta-protein; | flurbiprofen | |
cholanic acid | 5beta-cholanic acids; cholanic acid | ||
marimastat | marimastat : A secondary carboxamide resulting from the foraml condensation of the carboxy group of (2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoic acid with the alpha-amino group of N,3-dimethyl-L-valinamide. marimastat: a matrix metalloproteinase inhibitor active in patients with advanced carcinoma of the pancreas, prostate, or ovary | hydroxamic acid; secondary carboxamide | antineoplastic agent; matrix metalloproteinase inhibitor |
n-(2-isobutyl-3-(n'-hydroxycarbonylamido)propanoyl)-o-methyltyrosinemethylamide | N-(2-isobutyl-3-(N'-hydroxycarbonylamido)propanoyl)-O-methyltyrosinemethylamide: RN given refers to the (S-(R*,S*))-isomer | ||
ilomastat | CS 610: matrix metalloproteinase inhibitor; structure in first source ilomastat : An N-acyl-amino acid obtained by formal condensation of the carboxy group of (2R)-2-[2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoic acid with the amino group of N-methyl-L-tryptophanamide. A cell permeable broad-spectrum matrix metalloproteinase (MMP) inhibitor | hydroxamic acid; L-tryptophan derivative; N-acyl-amino acid | anti-inflammatory agent; antibacterial agent; antineoplastic agent; EC 3.4.24.24 (gelatinase A) inhibitor; neuroprotective agent |
bb3497 | BB3497: peptide deformylase inhibitor; structure in first source | ||
3-((benzyl)(methylaminocarbonyl)methylaminocarbonyl)n-hydroxy-5-methylhexanamide | 3-((benzyl)(methylaminocarbonyl)methylaminocarbonyl)N-hydroxy-5-methylhexanamide: structure in first source | ||
t0901317 | T0901317: an LXRalpha and LXRbeta agonist | ||
benzyloxycarbonylleucyl-leucyl-leucine aldehyde | benzyloxycarbonylleucyl-leucyl-leucine aldehyde: proteasome inhibitor N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal : A tripeptide that is L-leucyl-L-leucyl-L-leucine in which the C-terminal carboxy group has been reduced to the corresponding aldehyde and the N-terminal amino group is protected as its benzyloxycarbonyl derivative. | amino aldehyde; carbamate ester; tripeptide | proteasome inhibitor |
prinomastat | prinomastat : A hydroxamic acid that is (3S)-N-hydroxy-2,2-dimethylthiomorpholine-3-carboxamide in which the hydrogen attached to the thiomorpholine nitrogen has been replaced by a [4-(pyridin-4-yloxy)phenyl]sulfonyl group. It is a selective inhibitor with of matrix metalloproteinases (MMPs) 2, 3, 9, 13, and 14. prinomastat: a diazepine-based hydroxamic acid inhibitor; matrix metalloproteinase (MMP) inhibitor; angiogenesis inhibitor; | aromatic ether; hydroxamic acid; pyridines; sulfonamide; thiomorpholines | antineoplastic agent; EC 3.4.24.35 (gelatinase B) inhibitor; matrix metalloproteinase inhibitor |
isoliquiritigenin | chalcones | antineoplastic agent; biological pigment; EC 1.14.18.1 (tyrosinase) inhibitor; GABA modulator; geroprotector; metabolite; NMDA receptor antagonist | |
rs-130830 | RS-130830: orally-active broad-spectrum matrix metalloproteinase inhibitor | ||
tmi-1 | |||
n-(n-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester | DAPT : A dipeptide consisting of alanylphenylglycine derivatised as a 3,5-difluorophenylacetamide at the amino terminal and a tert-butyl ester at the carboxy terminal. A gamma-secretase inhibitor. | carboxylic ester; difluorobenzene; dipeptide; tert-butyl ester | EC 3.4.23.46 (memapsin 2) inhibitor |
sulindac sulfide | sulindac sulfide : An aryl sulfide that is a metabolite of sulindac. A non-steroidal anti-inflammatory drug, which also has anticancer activity. sulindac sulfide: sulfated analog of indomethacin & inhibitor of prostaglandin synthesis in vitro; RN given refers to cpd without isomeric designation; structure given in first source | aryl sulfide; monocarboxylic acid; organofluorine compound | antineoplastic agent; apoptosis inducer; non-steroidal anti-inflammatory drug |
batimastat | batimastat : A secondary carboxamide resulting from the formal condensation of the carboxy group of (2S,3R)-5-methyl-3-{[(2S)-1-(methylamino)-1-oxo-3-phenylpropan-2-yl]carbamoyl}-2-[(thiophen-2-ylsulfanyl)methyl]hexanoic acid with the amino group of hydroxylamine. It a broad-spectrum matrix metalloprotease inhibitor. batimastat: structure given in first source; a synthetic matrix metalloproteinase inhibitor | hydroxamic acid; L-phenylalanine derivative; organic sulfide; secondary carboxamide; thiophenes; triamide | angiogenesis inhibitor; antineoplastic agent; matrix metalloproteinase inhibitor |
pepstatin | pepstatin: inhibits the aspartic protease endothiapepsin | pentapeptide; secondary carboxamide | bacterial metabolite; EC 3.4.23.* (aspartic endopeptidase) inhibitor |
l 685458 | L 685458: a gamma-secretase inhibitor; structure in first source L-685,458 : A peptide and carboxamide that is L-leucyl-L-phenylalaninamide, L-Leu-L-Phe-NH2, which has been acylated on the N-terminus by a Phe-Phe hydroxyethylene dipeptide isotere, 2R-benzyl-5S-tert-butoxycarbonylamino-4R-hydroxy-6-phenylhexanoic acid. Compounds based on the structure of L-685,458 are potent inhibitors of gamma-secretase, which mediates the final catalytic step that generates the amyloid beta-peptide (Abeta), which assembles into the neurotoxic aggregates in the brains of sufferers of Alzheimer's disease. | carbamate ester; monocarboxylic acid amide; peptide; secondary alcohol | EC 3.4.23.46 (memapsin 2) inhibitor; peptidomimetic |
ik 682 | IK 682: inhibits TNF-alpha converting enzyme; structure in first source | hydroxamic acid; pyrrolidin-2-ones; quinolines | |
mk 0752 | |||
epigallocatechin-3-o-(3''-o-methyl)-gallate | catechin | ||
ro 32-3555 | Ro 32-3555: structure given in first source | ||
ly 450139 | peptide | ||
abt-770 | ABT-770: structure in first source | ||
sb 3ct compound | SB 3CT compound: a matrix metalloproteinase-2 inhibitor; structure in first source | aromatic ether | |
pd 166793 | |||
sc 78080 | |||
chf 5074 | 1-(3',4'-dichloro-2-fluoro(1,1'-biphenyl)-4-yl)cyclopropanecarboxylic acid: a beta-amyloid(1-42) lowering agent; structure in first source | ||
arp-100 | |||
ly 411575 | dibenzoazepine; difluorobenzene; lactam; secondary alcohol | EC 3.4.23.46 (memapsin 2) inhibitor | |
s 3304 | S 3304: structure in first source | ||
4-(2-((1r)-1-(((4-chlorophenyl)sulfonyl)-2,5-difluoroanilino)ethyl)-5-fluorophenyl)butanoic acid | sulfonamide | ||
begacestat | |||
N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamide | N(2)-([biphenyl]-4-ylsulfonyl)-N-hydroxy-N(2)-isopropoxy-D-valinamide : A hydroxamic acid that is N-hydroxy-D-valinamide in which the alpha-amino group has been substituted by isopropoxy and [biphenyl]-4-ylsulfonyl groups. A selective matrix metalloproteinase-2 (MMP-2) inhibitor, it is one of the most potent inducers of autophagy. Its physiological roles include angiogenesis, cancer metastasis, embryogenesis, tissue remodeling in development, and wound healing. | D-valine derivative; hydroxamic acid | antineoplastic agent; autophagy inducer; EC 3.4.24.24 (gelatinase A) inhibitor; melanin synthesis inhibitor |
bms-566394 | BMS-566394: structure in first source | ||
e 2012 | |||
mrk 560 | MRK 560: a gamma-secretase inhibitor; MRK-560 is the (cis)-isomer; structure in first source | ||
incb3619 | INCB3619: ADAM inhibitor; structure in first source | ||
pf-429242 | PF-429242: a subtilisin kexin isozyme-1/site-1 protease inhibitor | ||
grassystatin a | grassystatin A: isolated from a cyanobacterium, identified as Lyngbya cf.; structure in first source | ||
1, 3-di-(n-carboxybenzoyl-leucyl-leucyl)amino acetone | 1, 3-di-(N-carboxybenzoyl-leucyl-leucyl)amino acetone: structure in first source | ||
pf 3084014 | nirogacestat : A member of the class of imidazoles that is 1H-imidazole substituted by a 1-[(2,2-dimethylpropyl)amino]-2-methylpropan-2-yl group at position 1 and a {N-[(2S)-6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl]-L-norvalyl}amino group at position 4. It is a gamma-secretase inhibitor whose hydrobromide salt is indicated for adult patients with progressing desmoid tumours who require systemic treatment. nirogacestat: an antineoplastic agent | ||
bms 708163 | BMS 708163: structure in first source | oxadiazole; ring assembly | |
ro 4929097 | dibenzoazepine; dicarboxylic acid diamide; lactam; organofluorine compound | EC 3.4.23.46 (memapsin 2) inhibitor | |
jnj 40418677 | |||
(r)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1h-pyrazolo(4,3-c)quinoline | (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo(4,3-c)quinoline: gamma secretase inhibitor; structure in first source | ||
minocycline | minocycline : A tetracycline analogue having a dimethylamino group at position 7 and lacking the methyl and hydroxy groups at position 5. Minocycline: A TETRACYCLINE analog, having a 7-dimethylamino and lacking the 5 methyl and hydroxyl groups, which is effective against tetracycline-resistant STAPHYLOCOCCUS infections. | ||
guanosine diphosphate | Guanosine Diphosphate: A guanine nucleotide containing two phosphate groups esterified to the sugar moiety. | guanosine 5'-phosphate; purine ribonucleoside 5'-diphosphate | Escherichia coli metabolite; mouse metabolite; uncoupling protein inhibitor |