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Gamma-secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44. Subunits and assembly The gamma secretase complex consists of four individual proteins: PSEN1 (presenilin-1), nicastrin, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Recent eviden ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Presenilin-1
Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease. Structure Presenilin possesses a 9 transmembrane domain topology, with an extracellular C-terminus and a cytosolic N-terminus. Presenilin undergoes endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans. Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments. When presenilin 1 is overexpressed, the full length protein accumulates in an inactive form. Based on evidence that a gamma-secretase inhibitor binds to the fragments, the cleaved presenilin complex is considered to be the active form. Function ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
PSEN1
Presenilin-1 (PS-1) is a presenilin protein that in humans is encoded by the ''PSEN1'' gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease. Structure Presenilin possesses a 9 transmembrane domain topology, with an extracellular C-terminus and a cytosolic N-terminus. Presenilin undergoes endo-proteolytic processing to produce ~27-28 kDa N-terminal and ~16-17 kDa C-terminal fragments in humans. Furthermore, presenilin exists in the cell mainly as a heterodimer of the C-terminal and N-terminus fragments. When presenilin 1 is overexpressed, the full length protein accumulates in an inactive form. Based on evidence that a gamma-secretase inhibitor binds to the fragments, the cleaved presenilin complex is considered to be the active form. Function ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Presenilin
Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called '' PSEN1'' (located on chromosome 14 in humans) that codes for presenilin 1 (PS-1) and '' PSEN2'' (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm ''C. elegans'' has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1. Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. Cleavage of presenilin 1 can be ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Notch Signaling
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animals. Mammals possess four different Notch proteins, notch receptors, referred to as NOTCH1, NOTCH2, Notch 3, NOTCH3, and NOTCH4. The notch receptor is a single-pass Cell surface receptor, transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region. Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by NUMB (gene), Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development. Notch signaling is dysregulated in many cancers, and faulty notch signaling is implicated in many diseases, including T-cell acute lymphoblastic leukemia (Pre ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Intramembrane Protease
Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP). Intramembrane proteases are not evolutionarily related to classical soluble proteases, having evolved their catalytic sites by convergent evolution. Although only recently discovered, intramembrane proteases are of significant research interest because of their major biological functions and their relevance to human disease. Classification There are four groups of intramembrane proteases, distinguished by their catalytic mechanism: *Metalloproteases: ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Nicastrin
Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the ''NCSTN'' gene. Function Nicastrin (abbreviated NCT) is a protein that is part of the gamma secretase protein complex, which is one of the proteases involved in processing amyloid precursor protein (APP) to the short Alzheimer's disease-associated peptide amyloid beta. The other proteins in the complex are PSEN1 (presenilin-1), which is the catalytically active component of the complex, APH-1 (anterior pharynx-defective 1), and PEN-2 (presenilin enhancer 2). Nicastrin itself is not catalytically active, but instead promotes the maturation and proper trafficking of the other proteins in the complex, all of which undergo significant post-translational modification before becoming active in the cell. Nicastrin has also been identified as a regulator of neprilysin, an enzyme involved in the degradation of amyloid beta fragment. History The protein was named after the Italian country Nicastro, reflecting th ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
APH-1
APH-1 (anterior pharynx-defective 1) is a protein gene product originally identified in the Notch signaling pathway in ''Caenorhabditis elegans'' as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Beta Secretase
Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the ''BACE1'' gene. Expression of BACE1 is observed mainly in neurons. BACE1 is an aspartic acid protease important in the formation of myelin sheaths in peripheral nerve cells: in mice the expression of BACE1 is high in the postnatal stages, when myelination occurs. * The transmembrane protein contains two active site aspartate residues in its extracellular protein domain and may function as a dimer, its cytoplasmic tail is required for the correct maturation and an efficient intracellular trafficking, but doesn't affect the activity. It is produced as a pro-enzyme, the endoproteolitc removal occurs after BACE leaves Endoplasmic reticulum, in the Golgi apparatus. In addition the pro-peptide receives additional sugars to increase t ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Amyloid Beta
Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers (known as "seeds") can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold. A study has suggested that APP and its amyloid potential is of ancient origins, dating as far back a ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Amyloid Precursor Protein
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many biological tissue, tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene ''APP'' and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose Amyloid#Structure, amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Genetics Amyloid-beta precursor protein is an ancient and highly Conserved sequence, conserved protein. In humans, the gene ''APP'' is located on chromosome 21 and contains 18 exons spanning 290 kilobases. Several alternative splicing isoforms of APP have been observed in humans, ranging in len ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
PEN-2
PENSEN, formally PEN-2 (presenilin enhancer 2), is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D- Y- L- S- F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex. PEN-2 binds to metformin at therapeutic concentration and may be responsible for its AMPK-activating effects. PEN2-metformin in turn binds to ATP6AP1 to inhibit v-ATPase Vacuolar-type ATP ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Ephrin-B2
Ephrin-B2 is a protein that in humans is encoded by the ''EFNB2'' gene. Function This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNB class ephrin which binds to the EPHB4 and EPHA3 receptors. Cancer EFNB2 gene has been observed progressively downregulated in Human papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, EFNB2 is likely to be associated with tumorigenesis and may be a potent ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
