Amyloid-beta precursor protein
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Aliases | APP, AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, amyloid beta precursor protein, preA4, alpha-sAPP | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 104760; MGI: 88059; HomoloGene: 56379; GeneCards: APP; OMA:APP - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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![](http://upload.wikimedia.org/wikipedia/en/thumb/6/66/Relative_transport_of_negatively_charged%2C_APP-C_and_glycine_beads_in_the_squid_giant_axon.jpg/220px-Relative_transport_of_negatively_charged%2C_APP-C_and_glycine_beads_in_the_squid_giant_axon.jpg)
Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor[5] and has been implicated as a regulator of synapse formation,[6] neural plasticity,[7] antimicrobial activity,[8] and iron export.[9] It is coded for by the gene APP and regulated by substrate presentation.[10] APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.
Genetics
Amyloid-beta precursor protein is an ancient and highly conserved protein.[11] In humans, the gene APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases.[12][13] Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 639 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.[14] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms),[15] and all mammals.[16] 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.[16]
Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease.[17][18][19][20] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.[21]
A mutation (A673T) in the APP gene protects against Alzheimer's disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro.[22]
Structure
![](http://upload.wikimedia.org/wikipedia/commons/thumb/1/13/2fjz_app.png/250px-2fjz_app.png)
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/58/1rw6_e2_app.png/260px-1rw6_e2_app.png)
A number of different structural domains that fold mostly on their own have been found in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together.[24] A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain.[25] The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain,[26] the copper-binding domain,[27] the complete E1 domain[24] and the E2 domain.[23]
Isoform diversity
Amyloid-beta precursor protein is highly versatile with several isoforms generated through alternative splicing of its mRNA. The primary isoforms include APP695, APP751, and APP770, differing in their inclusion of certain exons, mainly exon 7 and 8. APP695 is predominantly expressed in neuronal cells and is crucial for normal neuronal function. APP751 and APP770 are more widely expressed in non-neuronal tissues but exhibit distinct expression patterns during neuron differentiation.[28] The differential expression of these isoforms plays a significant role in cellular processes such as neurodevelopment, synaptic plasticity, and the pathogenesis of Alzheimer's disease. Understanding the isoform diversity of APP is essential for deciphering its various physiological and pathological roles.
![](http://upload.wikimedia.org/wikipedia/commons/thumb/5/53/41598_2024_63005_Fig6_HTML.webp/220px-41598_2024_63005_Fig6_HTML.webp.png)
Post-translational processing
APP undergoes extensive post-translational modification including glycosylation, phosphorylation, sialylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments.[29] 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.[16] Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage 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.[30]
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.[31] Gamma secretase activity has also been associated with lipid rafts.[32] 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.[33]
Biological function
Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. Experimental models of Alzheimer's disease are commonly used by researchers to gain better understandings about the biological function of APP in disease pathology and progression.
Synaptic formation and repair
The most-substantiated role for APP is in synaptic formation and repair;[6] 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.[16] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.[34]
APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.[35] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.[36]
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.[37] The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia.
Somatic recombination
In neurons of the human brain, somatic recombination occurs frequently in the gene that encodes APP.[38] Neurons from individuals with sporadic Alzheimer's disease show greater APP gene diversity due to somatic recombination than neurons from healthy individuals.[38]
Anterograde neuronal transport
Molecules synthesized in the cell bodies of neurons must be conveyed outward to the distal synapses. This is accomplished via fast anterograde transport. It has been found that APP can mediate interaction between cargo and kinesin and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein.[39]
Additionally, it has been shown that the interaction between APP and kinesin is specific to the peptide sequence of APP.[40] In a recent experiment involving transport of peptide-conjugated colored beads, controls were conjugated to a single amino acid, glycine, such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that the terminal COOH moiety of peptides is not sufficient to mediate transport.
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.[9] It has been shown that a single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation.[41]
The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity.[42][43]
As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize the iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin).[44]
Hormonal regulation
The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression[45] and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC.[46][47][48]
AβPP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle.[49] It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production[50] and re-entry of post-mitotic neurons into the cell cycle.
Interactions
Amyloid precursor protein has been shown to interact with:
APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.[71]
References
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- ^ Zambrano N, Buxbaum JD, Minopoli G, Fiore F, De Candia P, De Renzis S, Faraonio R, Sabo S, Cheetham J, Sudol M, Russo T (Mar 1997). "Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer's beta-amyloid precursor proteins". The Journal of Biological Chemistry. 272 (10): 6399–405. doi:10.1074/jbc.272.10.6399. PMID 9045663.
- ^ Guénette SY, Chen J, Jondro PD, Tanzi RE (Oct 1996). "Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 93 (20): 10832–7. Bibcode:1996PNAS...9310832G. doi:10.1073/pnas.93.20.10832. PMC 38241. PMID 8855266.
- ^ Tanahashi H, Tabira T (Feb 1999). "Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein". Neuroscience Letters. 261 (3): 143–6. doi:10.1016/S0304-3940(98)00995-1. PMID 10081969. S2CID 54307954.
- ^ Trommsdorff M, Borg JP, Margolis B, Herz J (Dec 1998). "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". The Journal of Biological Chemistry. 273 (50): 33556–60. doi:10.1074/jbc.273.50.33556. PMID 9837937.
- ^ Chow N, Korenberg JR, Chen XN, Neve RL (May 1996). "APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein". The Journal of Biological Chemistry. 271 (19): 11339–46. doi:10.1074/jbc.271.19.11339. PMID 8626687.
- ^ Zheng P, Eastman J, Vande Pol S, Pimplikar SW (Dec 1998). "PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 95 (25): 14745–50. Bibcode:1998PNAS...9514745Z. doi:10.1073/pnas.95.25.14745. PMC 24520. PMID 9843960.
- ^ Wang B, Nguyen M, Breckenridge DG, Stojanovic M, Clemons PA, Kuppig S, Shore GC (Apr 2003). "Uncleaved BAP31 in association with A4 protein at the endoplasmic reticulum is an inhibitor of Fas-initiated release of cytochrome c from mitochondria". The Journal of Biological Chemistry. 278 (16): 14461–8. doi:10.1074/jbc.M209684200. PMID 12529377.
- ^ Lefterov IM, Koldamova RP, Lazo JS (Sep 2000). "Human bleomycin hydrolase regulates the secretion of amyloid precursor protein". FASEB Journal. 14 (12): 1837–47. doi:10.1096/fj.99-0938com. PMID 10973933. S2CID 44302063.
- ^ Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T (Jun 2004). "Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation". The Journal of Biological Chemistry. 279 (23): 24343–54. doi:10.1074/jbc.M401925200. PMID 15037614.
- ^ Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (Apr 1998). "Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein". The Journal of Biological Chemistry. 273 (17): 10485–95. doi:10.1074/jbc.273.17.10485. PMID 9553108.
- ^ Hashimoto T, Wakabayashi T, Watanabe A, Kowa H, Hosoda R, Nakamura A, Kanazawa I, Arai T, Takio K, Mann DM, Iwatsubo T (Apr 2002). "CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV". The EMBO Journal. 21 (7): 1524–34. doi:10.1093/emboj/21.7.1524. PMC 125364. PMID 11927537.
- ^ Ohsawa I, Takamura C, Kohsaka S (Mar 2001). "Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function". Journal of Neurochemistry. 76 (5): 1411–20. doi:10.1046/j.1471-4159.2001.00144.x. PMID 11238726. S2CID 83321033.
- ^ Chauhan VP, Ray I, Chauhan A, Wisniewski HM (May 1999). "Binding of gelsolin, a secretory protein, to amyloid beta-protein". Biochemical and Biophysical Research Communications. 258 (2): 241–6. doi:10.1006/bbrc.1999.0623. PMID 10329371.
- ^ Yan SD, Fu J, Soto C, Chen X, Zhu H, Al-Mohanna F, Collison K, Zhu A, Stern E, Saido T, Tohyama M, Ogawa S, Roher A, Stern D (Oct 1997). "An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease". Nature. 389 (6652): 689–95. Bibcode:1997Natur.389..689D. doi:10.1038/39522. PMID 9338779. S2CID 4343238.
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Further reading
- Beyreuther K, Pollwein P, Multhaup G, Mönning U, König G, Dyrks T, Schubert W, Masters CL (Sep 1993). "Regulation and expression of the Alzheimer's beta/A4 amyloid protein precursor in health, disease, and Down's syndrome". Annals of the New York Academy of Sciences. 695 (1 Transduction): 91–102. doi:10.1111/j.1749-6632.1993.tb23035.x. PMID 8239320. S2CID 22058428.
- Straub JE, Guevara J, Huo S, Lee JP (Jun 2002). "Long time dynamic simulations: exploring the folding pathways of an Alzheimer's amyloid Abeta-peptide". Accounts of Chemical Research. 35 (6): 473–81. doi:10.1021/ar010031e. PMID 12069633.
- Annaert W, De Strooper B (2003). "A cell biological perspective on Alzheimer's disease". Annual Review of Cell and Developmental Biology. 18 (1): 25–51. doi:10.1146/annurev.cellbio.18.020402.142302. PMID 12142279.
- Koo EH (Nov 2002). "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. S2CID 40411806.
- Van Nostrand WE, Melchor JP, Romanov G, Zeigler K, Davis J (Nov 2002). "Pathogenic effects of cerebral amyloid angiopathy mutations in the amyloid beta-protein precursor". Annals of the New York Academy of Sciences. 977 (1): 258–65. Bibcode:2002NYASA.977..258N. doi:10.1111/j.1749-6632.2002.tb04824.x. PMID 12480759. S2CID 22567664.
- Ling Y, Morgan K, Kalsheker N (Nov 2003). "Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease". The International Journal of Biochemistry & Cell Biology. 35 (11): 1505–35. doi:10.1016/S1357-2725(03)00133-X. PMID 12824062.
- Kerr ML, Small DH (Apr 2005). "Cytoplasmic domain of the beta-amyloid protein precursor of Alzheimer's disease: function, regulation of proteolysis, and implications for drug development". Journal of Neuroscience Research. 80 (2): 151–9. doi:10.1002/jnr.20408. PMID 15672415. S2CID 31985212.
- Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX (Jun 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. PMC 2517409. PMID 15910549.
- Tickler AK, Wade JD, Separovic F (Aug 2005). "The role of Abeta peptides in Alzheimer's disease". Protein and Peptide Letters. 12 (6): 513–9. doi:10.2174/0929866054395905. PMID 16101387.
- Reinhard C, Hébert SS, De Strooper B (Dec 2005). "The amyloid-beta precursor protein: integrating structure with biological function". The EMBO Journal. 24 (23): 3996–4006. doi:10.1038/sj.emboj.7600860. PMC 1356301. PMID 16252002.
- Watson D, Castaño E, Kokjohn TA, Kuo YM, Lyubchenko Y, Pinsky D, Connolly ES, Esh C, Luehrs DC, Stine WB, Rowse LM, Emmerling MR, Roher AE (Dec 2005). "Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer's disease". Neurological Research. 27 (8): 869–81. doi:10.1179/016164105X49436. hdl:11336/43663. PMID 16354549. S2CID 25687818.
- Calinisan V, Gravem D, Chen RP, Brittin S, Mohandas N, Lecomte MC, Gascard P (2006). "New insights into potential functions for the protein 4.1 superfamily of proteins in kidney epithelium". Frontiers in Bioscience. 11 (1): 1646–66. doi:10.2741/1911. PMID 16368544. S2CID 26325962.
- Vetrivel KS, Thinakaran G (Jan 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. S2CID 35965729.
- Gallo C, Orlassino R, Vineis C (Feb 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 (Aug 2006). "Does the p75 neurotrophin receptor mediate Abeta-induced toxicity in Alzheimer's disease?". Journal of Neurochemistry. 98 (3): 654–60. doi:10.1111/j.1471-4159.2006.03905.x. PMID 16893414. S2CID 20879380.
- Menéndez-González M, Pérez-Pinera P, Martínez-Rivera M, Calatayud MT, Blázquez Menes B (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. S2CID 45002038.
- Neve RL, McPhie DL (Apr 2007). "Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (4): 430–7. doi:10.1016/j.bbadis.2006.10.008. PMC 1862818. PMID 17113271.
- Chen X, Stern D, Yan SD (Dec 2006). "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 (Apr 2007). "Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1772 (4): 438–45. doi:10.1016/j.bbadis.2006.11.007. PMC 1876750. PMID 17215111.
- Wolfe MS (Feb 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 Reports. 8 (2): 136–40. doi:10.1038/sj.embor.7400896. PMC 1796780. PMID 17268504.
External links
![](http://upload.wikimedia.org/wikipedia/en/thumb/4/4a/Commons-logo.svg/30px-Commons-logo.svg.png)
- GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease
- Amyloid+Protein+Precursor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Entrez Gene: APP amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
- Human APP genome location and APP gene details page in the UCSC Genome Browser.
- v
- t
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- 1aap: X-RAY CRYSTAL STRUCTURE OF THE PROTEASE INHIBITOR DOMAIN OF ALZHEIMER'S AMYLOID BETA-PROTEIN PRECURSOR
- 1amb: SOLUTION STRUCTURE OF RESIDUES 1-28 OF THE AMYLOID BETA-PEPTIDE
- 1amc: SOLUTION STRUCTURE OF RESIDUES 1-28 OF THE AMYLOID BETA-PEPTIDE
- 1aml: THE ALZHEIMER`S DISEASE AMYLOID A4 PEPTIDE (RESIDUES 1-40)
- 1ba4: THE SOLUTION STRUCTURE OF AMYLOID BETA-PEPTIDE (1-40) IN A WATER-MICELLE ENVIRONMENT. IS THE MEMBRANE-SPANNING DOMAIN WHERE WE THINK IT IS? NMR, 10 STRUCTURES
- 1ba6: SOLUTION STRUCTURE OF THE METHIONINE-OXIDIZED AMYLOID BETA-PEPTIDE (1-40). DOES OXIDATION AFFECT CONFORMATIONAL SWITCHING? NMR, 10 STRUCTURES
- 1brc: RELOCATING A NEGATIVE CHARGE IN THE BINDING POCKET OF TRYPSIN
- 1ca0: BOVINE CHYMOTRYPSIN COMPLEXED TO APPI
- 1iyt: Solution structure of the Alzheimer's disease amyloid beta-peptide (1-42)
- 1mwp: N-TERMINAL DOMAIN OF THE AMYLOID PRECURSOR PROTEIN
- 1owt: Structure of the Alzheimer's disease amyloid precursor protein copper binding domain
- 1rw6: human APP core domain
- 1taw: BOVINE TRYPSIN COMPLEXED TO APPI
- 1tkn: Solution structure of CAPPD*, an independently folded extracellular domain of human Amyloid-beta Precursor Protein
- 1z0q: Aqueous Solution Structure of the Alzheimer's Disease Abeta Peptide (1-42)
- 1zjd: Crystal Structure of the Catalytic Domain of Coagulation Factor XI in Complex with Kunitz Protease Inhibitor Domain of Protease Nexin II
- 2beg: 3D Structure of Alzheimer's Abeta(1-42) fibrils
- 2fjz: Structure of the Alzheimer's Amyloid Precursor Protein (APP) copper binding domain (residues 133 to 189) in 'small unit cell' form, metal-free
- 2fk1: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, Cu(II)-bound
- 2fk2: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, Cu(I)-bound
- 2fk3: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'large unit cell' form
- 2fkl: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain (Residues 126- 189 of APP)
- 2fma: Structure of the Alzheimer's Amyloid Precursor Protein (APP) Copper Binding Domain in 'small unit cell' form, atomic resolution
- 2g47: Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-40)