Difference between revisions of "Amyloid precursor protein"

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Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
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PDB rendering based on 1aap.
Identifiers
SymbolsAPP; AAA; ABETA; ABPP; AD1; APPI; CTFgamma; CVAP; PN2
External IDsOMIM: 104760 MGI: 88059 HomoloGene: 56379 GeneCards: APP Gene
RNA expression pattern
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More reference expression data
Orthologs
SpeciesHumanMouse
Entrez35111820
EnsemblENSG00000142192ENSMUSG00000022892
UniProtP05067Q8BPC7
RefSeq (mRNA)NM_000484NM_007471
RefSeq (protein)NP_000475NP_031497
Location (UCSC)Chr 21:
26.17 - 26.47 Mb		Chr 16:
84.84 - 85.06 Mb
PubMed search[1][2]
File:2fjz app.png
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.
File:1rw6 e2 app.png
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], neural plasticity[3] and iron export.[4] APP is best known and most commonly studied as the precursor molecule whose proteolysis generates beta amyloid (Aβ), 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.

Genetics

In humans, the gene for APP is located on chromosome 21 and contains at least 18 exons in 240 kilobases.[5][6] 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.[7] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.[8] 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.[8]

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.[9][10][11] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.[12]

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, linked by a acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together.[13] A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain.[14] The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain[15], the copper-binding domain[16], the complete E1 domain[13] and the E2 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.[17] 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.[8] 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.[18]

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.[19] Gamma secretase activity has also been associated with lipid rafts.[20] 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.[21]

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive.

Synaptic formation and repair

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.[8] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.[22] APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[23] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.[24] The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques.[25] The data indicates that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may effect physiological deficits that contribute to dementia.

Iron export

A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin, facilitating iron export through interaction with ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's.[4]

Arthritis

Recently amyloid precursor protein (APP) origin was demonstrated with arthritogenic animals. The source noted is breakdown of immune complexes, where the amyloid aggregates are left degraded and binds together to form coil like feature and does not carried to circulation. Finally it induces secondary inflammation which may cause local damage.[26]

Interactions

Amyloid precursor protein has been shown to interact with APBA3,[27][28] CLSTN1,[29][30] APPBP1,[31] Gelsolin,[32] BCAP31,[33] Caveolin 1,[34] FBLN1,[35] Collagen, type XXV, alpha 1,[36] APBB1,[37][38][39][40][41] APBA2,[27][30][42] APBA1,[27][37] APPBP2,[43] HSD17B10,[44] BLMH[45] and SHC1.[46]

One group of scientists reports that APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.[47]

References

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Further reading

External links

Common amyloid forming proteins
Serum amyloid A  · Transthyretin  · Beta-2 microglobulin  · Bence Jones protein  · Amyloid precursor protein  · Beta amyloid  · Amylin
Systemic amyloidosis
Organ-limited amyloidosis
ca:Proteïna precursora amiloide

de:Amyloid-Precursor-Protein es:Proteína precursora amiloidea fr:Protéine précurtrice de l'amyloïde ru:Предшественник бета-амилоида

fi:Amyloidiprekursoriproteiini
  1. ↑ 1.0 1.1 PDB 1RW6; Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  3. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  4. ↑ 4.0 4.1 Duce JA; et al. (2010). "Iron-Export Ferroxidase Activity of β- Amyloid Precursor Protein Is Inhibited by Zinc in Alzheimer's Disease". Cell. doi:10.1016/j.cell.2010.08.014. 
  5. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  6. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  7. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  8. ↑ 8.0 8.1 8.2 8.3 Zheng H, Koo EH (2006). "The amyloid precursor protein: beyond amyloid". Mol Neurodegener. 1: 5. doi:10.1186/1750-1326-1-5. PMC 1538601 Freely accessible. PMID 16930452. 
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  10. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  11. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  12. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  13. ↑ 13.0 13.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.; see also PDB ID 3KTM
  14. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  15. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.; see also PDB ID 1MWP
  16. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.; See also 2007 PDB IDs 2FJZ, 2FK2, 2FKL.
  17. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  18. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  19. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  20. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  21. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  22. ↑ Selkoe D, Kopan R (2003). "Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration". Annu. Rev. Neurosci. 26: 565–97. doi:10.1146/annurev.neuro.26.041002.131334. PMID 12730322. 
  23. ↑ 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. doi:10.1016/S0306-4522(98)00645-9. PMID 10338291. 
  24. ↑ 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
  25. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  26. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  27. ↑ 27.0 27.1 27.2 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  28. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  29. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  30. ↑ 30.0 30.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  31. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  32. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  33. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  34. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  35. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  36. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  37. ↑ 37.0 37.1 Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  38. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  39. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  40. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  41. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  42. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  43. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  44. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  45. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  46. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
  47. ↑ Lua error in package.lua at line 80: module 'Module:Citation/CS1/Suggestions' not found.
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