Amyloid precursor protein

1AAP, 1AMB, 1AMC, 1AML, 1BA4, 1BA6, 1BJB, 1BJC, 1BRC, 1CA0, 1HZ3, 1IYT, 1MWP, 1OWT, 1QCM, 1QWP, 1QXC, 1QYT, 1TAW, 1TKN, 1X11, 1Z0Q, 1ZJD, 2BEG, 2BP4, 2FJZ, 2FK1, 2FK2, 2FK3, 2FKL, 2FMA, 2G47, 2IPU, 2LFM, 2LLM, 2LMN, 2LMO, 2LMP, 2LMQ, 2LOH, 2LP1, 2OTK, 2R0W, 2WK3, 2Y29, 2Y2A, 2Y3J, 2Y3K, 2Y3L, 3AYU, 3DXC, 3DXD, 3DXE, 3GCI, 3IFL, 3IFN, 3IFO, 3IFP, 3JTI, 3KTM, 3L33, 3L81, 3MOQ, 3NYL, 3SV1, 3U0T, 3UMH, 3UMI, 3UMK, 4HIX, 1ZE7, 1ZE9, 2LNQ, 2LZ3, 2LZ4, 2M4J, 2M9R, 2M9S, 2MGT, 2MJ1, 2MPZ, 2MVX, 2MXU, 3BAE, 3BKJ, 3JQ5, 3JQL, 3MXC, 3NYJ, 3OVJ, 3OW9, 4JFN, 4M1C, 4MDR, 4NGE, 4OJF, 4ONF, 4ONG, 4PQD, 4PWQ, 4MVI, 4MVK, 4MVL, 4XXD, 5CSZ, 5AMB, 5AEF, 5AM8, 5BUO, 5HOY, 5HOW, 5HOX, 5KK3, 5C67, 2NAO35111820ENSG00000142192ENSMUSG00000022892P05067P12023NM_001136131NM_001204301NM_001204302NM_001204303NM_201413NM_001198823NM_001198824NM_001198825NM_001198826NM_007471NP_001191230NP_001191231NP_001191232NP_958816NP_958817NP_001185752NP_001185753NP_001185754NP_001185755NP_031497Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity , and iron export. APP is best known as the precursor molecule whose proteolysis generates beta amyloid (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.1aap: X-RAY CRYSTAL STRUCTURE OF THE PROTEASE INHIBITOR DOMAIN OF ALZHEIMER'S AMYLOID BETA-PROTEIN PRECURSOR1amb: SOLUTION STRUCTURE OF RESIDUES 1-28 OF THE AMYLOID BETA-PEPTIDE1amc: SOLUTION STRUCTURE OF RESIDUES 1-28 OF THE AMYLOID BETA-PEPTIDE1aml: THE ALZHEIMER`S DISEASE AMYLOID A4 PEPTIDE (RESIDUES 1-40)1ba4: THE SOLUTION STRUCTURE OF AMYLOID BETA-PEPTIDE (1-40) IN A WATER-MICELLE ENVIRONMENT. IS THE MEMBRANE-SPANNING DOMAIN WHERE WE THINK IT IS? NMR, 10 STRUCTURES1ba6: SOLUTION STRUCTURE OF THE METHIONINE-OXIDIZED AMYLOID BETA-PEPTIDE (1-40). DOES OXIDATION AFFECT CONFORMATIONAL SWITCHING? NMR, 10 STRUCTURES1brc: RELOCATING A NEGATIVE CHARGE IN THE BINDING POCKET OF TRYPSIN1ca0: BOVINE CHYMOTRYPSIN COMPLEXED TO APPI1iyt: Solution structure of the Alzheimer's disease amyloid beta-peptide (1-42)1mwp: N-TERMINAL DOMAIN OF THE AMYLOID PRECURSOR PROTEIN1owt: Structure of the Alzheimer's disease amyloid precursor protein copper binding domain1rw6: human APP core domain1taw: BOVINE TRYPSIN COMPLEXED TO APPI1tkn: Solution structure of CAPPD*, an independently folded extracellular domain of human Amyloid-beta Precursor Protein1z0q: Aqueous Solution Structure of the Alzheimer's Disease Abeta Peptide (1-42)1zjd: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Kunitz Protease Inhibitor Domain of Protease Nexin II2beg: 3D Structure of Alzheimer's Abeta(1-42) fibrils2fjz: Structure of the Alzheimer's Amyloid Precursor Protein (APP) copper binding domain (residues 133 to 189) in 'small unit cell' form, metal-free2fk1: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, Cu(II)-bound2fk2: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, Cu(I)-bound2fk3: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'large unit cell' form2fkl: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain (Residues 126- 189 of APP)2fma: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, atomic resolution2g47: Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-40) Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity , and iron export. APP is best known as the precursor molecule whose proteolysis generates beta amyloid (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. APP is an ancient and highly conserved protein. In humans, the gene for 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 preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease. Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals. The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions. Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease. For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ. A mutation (A673T) in the APP gene protects against Alzheimer’s disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro. A number of distinct, largely independently-folding structural domains have been identified in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together. A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain. The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain, the copper-binding domain, the complete E1 domain and the E2 domain. APP undergoes extensive post-translational modification including glycosylation, phosphorylation, sialylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments. It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis. Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's. The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. Gamma secretase activity has also been associated with lipid rafts. The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease.