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07-SEPTEMBER-2008 03:17:44 - Amyloid precursor protein Amyloid beta A4 precursor protein peptidase nexin-II, Alzheimer disease PDB rendering based on 1aap. Available structures: 1aap, 1amb, 1amc, 1aml, 1ba4, 1ba6, 1brc, 1ca0, 1iyt, 1mwp, 1owt, 1rw6, 1taw, 1tkn, 1z0q, 1zjd, 2beg, 2fjz, 2fk1, 2fk2, 2fk3, 2fkl, 2fma, 2g47 Identifiers Symbols APP; AAA; ABETA; ABPP; AD1; APPI; CTFgamma; CVAP; PN2 External IDs OMIM: 104760 MGI: 88059 HomoloGene: 56379 Gene ontology Molecular function: DNA binding serine-type endopeptidase inhibitor activity binding iron ion binding copper ion binding heparin binding zinc ion binding identical protein binding metal ion binding Cellular component: extracellular region membrane fraction cytoplasm Golgi apparatus integral to plasma membrane coated pit cell surface membrane integral to membrane axon cytoplasmic vesicle neuromuscular junction ciliary rootlet apical part of cell perinuclear region of cytoplasm spindle midzone Biological process: G2 phase of mitotic cell cycle suckling behavior mRNA polyadenylation cellular copper ion homeostasis endocytosis apoptosis cell adhesion Notch signaling pathway axonogenesis mating behavior axon cargo transport adult locomotory behavior visual learning axon midline choice point recognition neuron remodeling dendrite development extracellular matrix organization and biogenesis forebrain development regulation of body size positive regulation of progression through mitotic cell cycle positive regulation of transcription from RNA polymerase II promoter collateral sprouting in the absence of injury regulation of synapse structure and activity regulation of balance neuromuscular process synaptic growth at neuromuscular junction smooth endoplasmic reticulum calcium ion homeostasis RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 351 11820 Ensembl ENSG00000142192 ENSMUSG00000022892 Uniprot P05067 Q8BPC7 Refseq NM_000484 mRNA NP_000475 protein NM_007471 mRNA NP_031497 protein Location Chr 21: 26.17 - 26.47 Mb Chr 16: 84.84 - 85.06 Mb Pubmed search 1 2 The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the CuI bound, CuII bound, and unbound conformations, which differ by only small changes in orientation. The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the CuI bound, CuII bound, and unbound conformations, which differ by only small changes in orientation. The extracellular E2 domain, a dimeric coiled coil and one of the most highly-conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans. The extracellular E2 domain, a dimeric coiled coil and one of the most highly-conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans.1 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 formation2 and neural plasticity.3 APP is best known and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta, a 39- to 42-amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Contents 1 Genetics 2 Structure 3 Post-translational processing 4 Biological function 5 References 6 Further reading 7 External links Genetics In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.45 Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 365 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.6 Homologous proteins have been identified in other organisms such as Drosophila fruit flies, C. elegans roundworms, and all mammals.7 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.7 Mutations in critical regions of Amyloid Precursor Protein, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease.8910 For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.11 Structure 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; E1 contains several subdomains including a growth factor-like domain GFLD, a metal-binding motif, and a serine protease inhibitor domain that is absent from the isoform differentially expressed in the brain.12 The E2 domain contains a coiled coil dimerization motif and may bind proteoglycans in the extracellular matrix.1 The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, including the copper-binding domain in multiple configurations and ion-binding states13 and the E2 dimerization domain.1 Post-translational processing APP undergoes extensive post-translational modification including glycosylation, phosphorylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.14 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.7 Cleavage by gamma secretase within the membrane-spanning domain 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.15 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.16 Gamma secretase activity has also been associated with lipid rafts.17 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.18 Biological function Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. The most-substantiated role for APP is in synaptic formation and repair;2 its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research.7 In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.19APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.20 On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.21 References ^ a b c Wang Y, Ha Y. 2006. The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain. Mol Cell 153:343-53. PMID 15304215 ^ a b Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. 2006. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci 2627:7212-21. PMID 16822978 ^ Turner PR, O'Connor K, Tate WP, Abraham WC. 2003. Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity, and memory. Prog Neurobiol 701:1-32. PMID 12927332 ^ Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y 1990. Genomic organization of the human amyloid beta-protein precursor gene Gene 87:257-263. PMID 2110105 ^ Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD. 1993. Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice Nat Genet 5:22-30. PMID 8220418 ^ Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT. 2007. Expression of APP pathway mRNAs and proteins in Alzheimer's disease. Brain Res Epub. PMID 17586478 ^ a b c d Zheng H, Koo EH. 2006. The amyloid precursor protein: beyond amyloid. Mol Neurodegener 3;1:5. PMID 16930452 ^ Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al. 1991. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 3496311:704-6. PMID 1671712 ^ Murrell J, Farlow M, Ghetti B, Benson MD. 1991. A mutation in the amyloid precursor protein associated with herary Alzheimer's disease. Science 2545028:97-9. PMID 1925564 ^ Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al. 1991. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 3536347:844-6. PMID 1944558 ^ Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. 1992. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature 3606405:672-4. PMID 1465129 ^ Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL. 1993. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci 13:3136-3142. PMID 8331390 ^ Kong GK, Galatis D, Barnham KJ, Polekhina G, Adams JJ, Masters CL, Cappai R, Parker MW, McKinstry WJ. 2005. Crystallization and preliminary crystallographic studies of the copper-binding domain of the amyloid precursor protein of Alzheimer's disease. Acta Crystallograph 61Pt 1:93-5. PMID 16508101. See also 2007 PDB IDs 2FJZ, 2FK2, 2FKL. ^ De Strooper B, Annaert W. 2000. Proteolytic processing and cell biological functions of the amyloid precursor protein. J Cell Sci 113 Pt 11:1857-70. PMID 10806097 ^ Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P. 2006. TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity. Nature 440:1208-1212. PMID 16641999 ^ Ehehalt R, Keller P, Haass C, Thiele C, Simons K. 2003. Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts. J Cell Biol 1601:113-23. PMID 12515826 ^ Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G. 2004. Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes. J Biol Chem 27943:44945-54. PMID 15322084 ^ Riddell DR, Christie G, Hussain I, Dingwall C. 2001. Compartmentalization of beta-secretase Asp2 into low-buoyant density, noncaveolar lipid rafts. Curr Biol 1116:1288-93. PMID 11525745 ^ Selkoe D, Kopan R. 2003. Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565-597. PMID 12730322 ^ Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M. 1999. No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice. Neuroscience 904:1207-16. PMID 10338291 ^ Matsuyama S, Teraoka R, Mori H, Tomiyama T. 2007. Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice. Neuroreport 1810:1083-7. PMID 17558301 Further reading Beyreuther K, Pollwein P, Multhaup G, et al. 1993. Regulation and expression of the Alzheimer's beta/A4 amyloid protein precursor in health, disease, and Down's syndrome.. Ann. N. Y. Acad. Sci. 695: 91-102. doi:10.1111/j.1749-6632.1993.tb23035.x. PMID 8239320. Straub JE, Guevara J, Huo S, Lee JP 2003. Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-peptide.. Acc. Chem. Res. 35 6: 473-81. doi:10.1021/ar010031e. PMID 12069633. Annaert W, De Strooper B 2003. A cell biological perspective on Alzheimer's disease.. Annu. Rev. Cell Dev. Biol. 18: 25-51. doi:10.1146/annurev.cellbio.18.020402.142302. PMID 12142279. Koo EH 2003. The beta-amyloid precursor protein APP and Alzheimer's disease: does the tail wag the dog?. Traffic 3 11: 763-70. doi:10.1034/j.1600-0854.2002.31101.x. PMID 12383342. Van Nostrand WE, Melchor JP, Romanov G, et al. 2003. Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor.. Ann. N. Y. Acad. Sci. 977: 258-65. PMID 12480759. Ling Y, Morgan K, Kalsheker N 2004. Amyloid precursor protein APP and the biology of proteolytic processing: relevance to Alzheimer's disease.. Int. J. Biochem. Cell Biol. 35 11: 1505-35. doi:10.1016/S1357-27250300133-X. PMID 12824062. Kerr ML, Small DH 2005. Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development.. J. Neurosci. Res. 80 2: 151-9. doi:10.1002/jnr.20408. PMID 15672415. Maynard CJ, Bush AI, Masters CL, et al. 2005. Metals and amyloid-beta in Alzheimer's disease.. International journal of experimental pathology 86 3: 147-59. doi:10.1111/j.0959-9673.2005.00434.x. PMID 15910549. Tickler AK, Wade JD, Separovic F 2005. The role of Abeta peptides in Alzheimer's disease.. Protein Pept. Lett. 12 6: 513-9. doi:10.2174/0929866054395905. PMID 16101387. Reinhard C, Hébert SS, De Strooper B 2006. The amyloid-beta precursor protein: integrating structure with biological function.. EMBO J. 24 23: 3996-4006. doi:10.1038/sj.emboj.7600860. PMID 16252002. Watson D, Castaño E, Kokjohn TA, et al. 2006. Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease.. Neurol. Res. 27 8: 869-81. doi:10.1179/016164105X49436. PMID 16354549. Calinisan V, Gravem D, Chen RP, et al. 2006. New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium.. Front. Biosci. 11: 1646-66. doi:10.2741/1911. PMID 16368544. Vetrivel KS, Thinakaran G 2006. Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments.. Neurology 66 2 Suppl 1: S69-73. doi:10.1212/01.wnl.0000192107.17175.39. PMID 16432149. Gallo C, Orlassino R, Vineis C 2006. Recurrent intraparenchimal haemorrhages in a patient with cerebral amyloidotic angiopathy: description of one autopsy case. Pathologica 98 1: 44-7. PMID 16789686. Coulson EJ 2006. Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?. J. Neurochem. 98 3: 654-60. doi:10.1111/j.1471-4159.2006.03905.x. PMID 16893414. Menéndez-González M, Pérez-Pinera P, Martínez-Rivera M, et al. 2006. APP processing and the APP-KPI domain involvement in the amyloid cascade.. Neuro-degenerative diseases 2 6: 277-83. doi:10.1159/000092315. PMID 16909010. Neve RL, McPhie DL 2007. Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis.. Biochim. Biophys. Acta 1772 4: 430-7. doi:10.1016/j.bbadis.2006.10.008. PMID 17113271. Chen X, Stern D, Yan SD 2007. Mitochondrial dysfunction and Alzheimer's disease.. Current Alzheimer research 3 5: 515-20. doi:10.2174/156720506779025215. PMID 17168650. Caltagarone J, Jing Z, Bowser R 2007. Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease.. Biochim. Biophys. Acta 1772 4: 438-45. doi:10.1016/j.bbadis.2006.11.007. PMID 17215111. Wolfe MS 2007. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease.. EMBO Rep. 8 2: 136-40. doi:10.1038/sj.embor.7400896. PMID 17268504. External links MeSH Amyloid+Protein+Precursor Entrez Gene: APP amyloid beta A4 precursor protein peptidase nexin-II, Alzheimer disease v d e Metabolic disease: amyloidosis E85, 277.3 Forms of amyloid Serum amyloid P component - Serum amyloid A - Transthyretin - Beta-2 microglobulin - Bence Jones protein/Multiple myeloma - Amyloid precursor protein/Beta amyloid - Amylin Systemic amyloidosis AL amyloidosis - AA amyloidosis - Haemodialysis-associated amyloidosis - Senile systemic amyloidosis - Finnish type amyloidosis - Familial Merranean fever Organ-limited amyloidosis heart: Cardiac amyloidosis brain: Familial amyloid neuropathy - Cerebral amyloid angiopathy - Alzheimer's disease kidney: Familial renal amyloidosis cutaneous: Primary cutaneous amyloidosis Retrieved from http://en..org/wiki/Amyloid_precursor_protein Categories: Genes on chromosome 21 | Human proteins | Metabolic disorders | Alzheimer's disease | Integral membrane proteins | Neurochemistry Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Español Français 中文 This page was last modified on 12 July 2008, at 11:14
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