Amyloid precursor protein

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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 as the precursor molecule whose proteolysis generates amyloid beta, a 39-42 amino acid peptide whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

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[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. Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.[6] Mutations in critical regions of APP, including the region that generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease. 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.[6]

[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.[7] 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[8] 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.[9] 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.[6] It is cleavage by gamma secretase within the membrane-spanning domain that generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but notably include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's.[10]

[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 well-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.[6] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.[11]APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[12]

[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. ^ a b c d Zheng H, Koo EH. (2006). The amyloid precursor protein: beyond amyloid. Mol Neurodegener 3;1:5. PMID 16930452
  7. ^ 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
  8. ^ 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.
  9. ^ 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
  10. ^ 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
  11. ^ Selkoe D, Kopan R. (2003). Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration. Annu Rev Neurosci 26:565-597. PMID 12730322
  12. ^ 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
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