Amyloid precursor protein

edit Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) 250px PDB rendering based on 1aap. Available structures PDB 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 GeneCards: APP Gene 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 Sources: Amigo / EGO RNA expression pattern 250px 250px 250px More reference expression data Orthologs Species Human Mouse Entrez 351 11820 Ensembl ENSG00000142192 ENSMUSG00000022892 UniProt P05067 Q8BPC7 RefSeq (mRNA) NM_000484 NM_007471 RefSeq (protein) NP_000475 NP_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.

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 and iron export. 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. 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. 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, are known to 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.

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. 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.

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. 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 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.

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; 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. In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch. APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation. 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. 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.

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.

Interactions

Amyloid precursor protein has been shown to interact with APBA3, CLSTN1, APPBP1, Gelsolin, BCAP31, Caveolin 1, FBLN1, Collagen, type XXV, alpha 1, APBB1, APBA2, APBA1, APPBP2, HSD17B10, BLMH and SHC1.

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

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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. doi:10.1111/j.1749-6632.2002.tb04824.x. PMID 12480759. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. PMC 1356301 Freely accessible. PMID 16252002. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. PMC 1862818 Freely accessible. 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. CS1 maint: Multiple names: authors list (link)
• 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. PMC 1876750 Freely accessible. PMID 17215111. CS1 maint: Multiple names: authors list (link)
• 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. PMC 1796780 Freely accessible. PMID 17268504. 

External links

• MeSH Amyloid+Protein+Precursor
• Entrez Gene: APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)

ca:Proteïna precursora amiloide fi:Amyloidiprekursoriproteiini