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APH-1
APH-1 (anterior pharynx-defective 1) is a protein originally identified in the round worm ''Caenorhabditis elegans'' as a regulator of the cell-surface localization of nicastrin in the Notch pathway, Notch signaling pathway. APH-1 homologs in other organisms, including humans (APH1A and APH1B), 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 protein folding, 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 acti ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Gamma Secretase
Gamma secretase is a multi-subunit protease complex, 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 protein folding, 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 signaling, 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 e ... [...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 the ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
PEN-2
PSENEN, 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 pathway, 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 (anatomy), lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif aspartate, D-tyrosine, Y-leucine, L-serine, S-phenylalanine, 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 AMP-activated protein kinase, AMPK ... [...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 ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Amyloid-beta Precursor Protein
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many 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 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 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 length from 639 to 770 amino acids, with certain isoforms pr ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Notch Proteins
__NOTOC__ __FORCETOC__ Notch proteins are a family of type 1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in animals. The Notch extracellular domain mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling. The Notch intracellular domain acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in ''Caenorhabditis elegans'' (''C.elegans'') and ''Drosophila melanogaster.'' Human hom ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Notch Signaling Pathway
The Notch signaling pathway is a highly Conserved sequence, conserved cell signaling system present in most animal, 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 leuke ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabolic reactions, DNA replication, Cell signaling, responding to stimuli, providing Cytoskeleton, structure to cells and Fibrous protein, organisms, and Intracellular transport, transporting molecules from one location to another. Proteins differ from one another primarily in their sequence of amino acids, which is dictated by the Nucleic acid sequence, nucleotide sequence of their genes, and which usually results in protein folding into a specific Protein structure, 3D structure that determines its activity. A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are rarely considered to be proteins and are commonly called pep ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
Transmembrane Domain
A transmembrane domain (TMD, TM domain) is a membrane-spanning protein domain. TMDs may consist of one or several alpha-helices or a transmembrane beta barrel. Because the interior of the lipid bilayer is hydrophobic, the amino acid residues in TMDs are often hydrophobic, although proteins such as membrane pumps and ion channels can contain polar residues. TMDs vary greatly in size and hydrophobicity; they may adopt organelle-specific properties. Functions of transmembrane domains Transmembrane domains are known to perform a variety of functions. These include: * Anchoring transmembrane proteins to the membrane. *Facilitating molecular transport of molecules such as ions and proteins across biological membranes; usually hydrophilic residues and binding sites in the TMDs help in this process. *Signal transduction across the membrane; many transmembrane proteins, such as G protein-coupled receptors, receive extracellular signals. TMDs then propagate those signals across the ... [...More Info...] [...Related Items...] OR: [Wikipedia] [Google] [Baidu] |
