Amyloid precursor protein

From Wikipedia, the free encyclopedia


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
Symbol(s) APP; AAA; ABETA; ABPP; AD1; APPI; CTFgamma; CVAP; PN2
External IDs OMIM: 104760 MGI: 88059 HomoloGene: 56379
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 Cu(I) bound, Cu(II) 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 Cu(I) bound, Cu(II) 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 formation[2] 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

[edit] Genetics

In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.[4][5] 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.[8][9][10] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.[11]

[edit] 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 states[13] and the E2 dimerization domain.[1]

[edit] 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]

[edit] 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.[19]APP 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]

[edit] References

  1. ^ 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 15(3):343-53. PMID 15304215
  2. ^ 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 26(27):7212-21. PMID 16822978
  3. ^ 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 70(1):1-32. PMID 12927332
  4. ^ 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
  5. ^ 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
  6. ^ 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
  7. ^ a b c d Zheng H, Koo EH. (2006). The amyloid precursor protein: beyond amyloid. Mol Neurodegener 3;1:5. PMID 16930452
  8. ^ 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 349(6311):704-6. PMID 1671712
  9. ^ Murrell J, Farlow M, Ghetti B, Benson MD. (1991). A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254(5028):97-9. PMID 1925564
  10. ^ 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 353(6347):844-6. PMID 1944558
  11. ^ 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 360(6405):672-4. PMID 1465129
  12. ^ 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
  13. ^ 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 61(Pt 1):93-5. PMID 16508101. See also 2007 PDB IDs 2FJZ, 2FK2, 2FKL.
  14. ^ 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
  15. ^ 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
  16. ^ 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 160(1):113-23. PMID 12515826
  17. ^ 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 279(43):44945-54. PMID 15322084
  18. ^ Riddell DR, Christie G, Hussain I, Dingwall C. (2001). Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts. Curr Biol 11(16):1288-93. PMID 11525745
  19. ^ Selkoe D, Kopan R. (2003). Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565-597. PMID 12730322
  20. ^ 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 90(4):1207-16. PMID 10338291
  21. ^ Matsuyama S, Teraoka R, Mori H, Tomiyama T. (2007). Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice. Neuroreport 18(10):1083-7. PMID 17558301

[edit] 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/S1357-2725(03)00133-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. 


[edit] External links

v • d • e
Metabolic disease: amyloidosis (E85, 277.3)
Forms of amyloid
Systemic amyloidosis
Organ-limited amyloidosis