Summary: Beta-amyloid peptide (beta-APP)
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Beta amyloid Edit Wikipedia article
||This article may be too technical for most readers to understand. (January 2011)|
|Beta-amyloid peptide (beta-APP)|
A partially folded structure of amyloid-beta(1 40) in an aqueous environment (pdb 2lfm)
|amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)|
Processing of the amyloid precursor protein
|Locus||Chr. 21 q21.2|
Amyloid beta (AÎ² or Abeta) is a peptide of 36â43 amino acids that is processed from the amyloid precursor protein (APP). While best known as a component of amyloid plaques in association with Alzheimer's disease, as AÎ² is the main component of certain deposits found in the brains of patients with Alzheimer's disease, evidence has been found that AÎ² is a highly multifunctional peptide with significant non-pathological activity. A recent study suggested that APP and its amyloid potential is of ancient origins, dating as far back as early deuterostomes.
 Normal activity
The normal function of AÎ² is not well understood. Though some animal studies have shown that the absence of AÎ² does not lead to any loss of physiological function, several potential activities have been discovered for AÎ², including activation of kinase enzymes, protection against oxidative stress, regulation of cholesterol transport, functioning as a transcription factor, and anti-microbial activity (potentially associated with AÎ²'s pro-inflammatory activity).
 Disease associations
AÎ² is the main component of amyloid plaques (deposits found in the brains of patients with Alzheimer's disease). Similar plaques appear in some variants of Lewy body dementia and in inclusion body myositis (a muscle disease), while AÎ² can also form the aggregates that coat cerebral blood vessels in cerebral amyloid angiopathy. The plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibers, a protein fold shared by other peptides such as the prions associated with protein misfolding diseases. Recent research suggests that soluble oligomeric forms of the peptide may be causative agents in the development of Alzheimer's disease. A number of genetic, cell biology, biochemical and animal studies support the concept that AÎ² plays a central role in the development of Alzheimerâs disease pathology.
Brain AÎ² is elevated in patients with sporadic Alzheimerâs disease. AÎ² is the main constituent of brain parenchymal and vascular amyloid; it contributes to cerebrovascular lesions and is neurotoxic. It is unresolved how AÎ² accumulates in the central nervous system and subsequently initiates the disease of cells. Some researchers have found that the AÎ² oligomers induce some of the symptoms of Alzheimer's Disease by competing with insulin for binding sites on the insulin receptor, thus impairing glucose metabolism in the brain. Significant efforts have been focused on the mechanisms responsible for AÎ² production, including the proteolytic enzymes alpha- and Î²-secretases which generate AÎ² from its precursor protein, APP (amyloid precursor protein). AÎ² circulates in plasma, cerebrospinal fluid (CSF) and brain interstitial fluid (ISF) mainly as soluble AÎ²40 Senile plaques contain both AÎ²40 and AÎ²42, while vascular amyloid is predominantly the shorter AÎ²40. Several sequences of AÎ² were found in both lesions. Generation of AÎ² in the CNS may take place in the neuronal axonal membranes after APP-mediated axonal transport of Î²-secretase and presenilin-1.
AÎ² is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function. APP can be processed by Î±-, Î²- and Î³-secretases; AÎ² protein is generated by successive action of the Î² and Î³ secretases. The Î³ secretase, which produces the C-terminal end of the AÎ² peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 36-43 amino acid residues in length. The most common isoforms are AÎ²40 and AÎ²42; the longer form is typically produced by cleavage that occurs in the endoplasmic reticulum, while the shorter form is produced by cleavage in the trans-Golgi network. The AÎ²40 form is the more common of the two, but AÎ²42 is the more fibrillogenic and is thus associated with disease states. Mutations in APP associated with early-onset Alzheimer's have been noted to increase the relative production of AÎ²42, and thus one suggested avenue of Alzheimer's therapy involves modulating the activity of Î² and Î³ secretases to produce mainly AÎ²40. AÎ² is destroyed by several amyloid-degrading enzymes including neprilysin.
Autosomal-dominant mutations in APP cause hereditary early-onset Alzheimer's disease (familial AD). This form of AD only accounts for no more than 10% of all cases, and the vast majority of AD is not accompanied by such mutations. However, familial Alzheimer disease is likely to result from altered proteolytic processing. Increases in either total AÎ² levels or the relative concentration of both AÎ²40 and AÎ²42 (where the former is more concentrated in cerebrovascular plaques and the latter in neuritic plaques) have been implicated in the pathogenesis of both familial and sporadic Alzheimer's disease. Due to its more hydrophobic nature, the AÎ²42 is the most amyloidogenic form of the peptide. However the central sequence KLVFFAE is known to form amyloid on its own, and probably forms the core of the fibril.
The "amyloid hypothesis", that the plaques are responsible for the pathology of Alzheimer's disease, is accepted by the majority of researchers but is by no means conclusively established. An alternative hypothesis is that amyloid oligomers rather than plaques are responsible for the disease. Mice that are genetically engineered to express oligomers but not plaques (APPE693Q) develop the disease. Furthermore mice that are in addition engineered to convert oligomers into plaques (APPE693Q X PS1ÎE9), are no more impaired than the oligomer only mice. Intra-cellular deposits of tau protein are also seen in the disease, and may also be implicated, as has aggregation of alpha synuclein.
Amyloid beta is commonly thought to be intrinsically unstructured, meaning that in solution it does not acquire a unique tertiary fold but rather populates a set of structures. As such, it cannot be crystallized and most structural knowledge on amyloid beta comes from NMR and molecular dynamics. Early NMR-derived models of a 26-aminoacid polypeptide from amyloid beta (AÎ² 10-35) show a collapsed coil structure devoid of significant secondary structure content, however, the most recent (2012) NMR structure of (AÎ² 1-40) has significant secondary and tertiary structure. Replica exchange molecular dynamics studies suggested that amyloid beta can indeed populate multiple discrete structural states; more recent studies identified a multiplicity of discrete conformational clusters by statistical analysis. By NMR-guided simulations, amyloid beta 1-40 and amyloid beta 1-42 also seem to feature highly different conformational states, with the C-terminus of amyloid beta 1-42 being more structured than that of the 1-40 fragment.
Structural information on the oligomeric state of amyloid beta is still sparse as of 2010. Low-temperature and low-salt conditions allowed to isolate pentameric disc-shaped oligomers devoid of beta structure. In contrast, soluble oligomers prepared in the presence of detergents seem to feature substantial beta sheet content with mixed parallel and antiparallel character, different from fibrils; computational studies suggest an antiparallel beta-turn-beta motif instead for membrane-embedded oligomers.
 Intervention strategies
Researchers in Alzheimer's disease have identified five strategies as possible interventions against amyloid:
- Î²-Secretase inhibitors. These work to block the first cleavage of APP outside of the cell.
- Î³-Secretase inhibitors (e. g. semagacestat). These work to block the second cleavage of APP in the cell membrane and would then stop the subsequent formation of AÎ² and its toxic fragments.
- Selective AÎ²42 lowering agents (e. g. tarenflurbil). These modulate Î³-secretase to reduce AÎ²42 production in favor of other (shorter) AÎ² versions.
Î²- and y-secretase are responsible for the generation of AÎ² from the release of the intracellular domain of APP, meaning that compounds that can partially inhibit the activity of either Î²- and y-secretase are highly sought after. In order to initiate partial inhibition of Î²- and y-secretase, a compound is needed that can block the large active site of aspartyl proteases while still being capable of bypassing the blood-brain barrier. To date, human testing has been avoided due to concern that it might interfere with signaling via Notch proteins and other cell surface receptors.
- Immunotherapy. This stimulates the host immune system to recognize and attack AÎ², or provide antibodies that either prevent plaque deposition or enhance clearance of plaques or AÎ² oligomers. Oligomerization is a chemical process that converts individual molecules into a chain consisting of a finite number of molecules. Prevention of oligomerization of AÎ² has been exemplified by active or passive AÎ² immunization. In this process antibodies to AÎ² are used to decrease cerebral plaque levels. This is accomplished by promoting microglial clearance and/or redistributing the peptide from the brain to systemic circulation. One such beta-amyloid vaccine that is currently in clinical trials is CAD106. Immunization with synthetic AÎ²1-42 has been shown to be beneficial in mice and displays low toxicity; however human trials have shown no significant differences. Thus, it is not yet effective in humans and requires further research. Specific findings show that the 20 amino acid SDPM1 protein binds tetramer forms of AÎ²(1-40)- and AÎ²(1-42)-amyloids and blocks subsequent AÎ² amyloid aggregation. It is important to note that this study was done in mice and that while it prevents further development of neuropathology it did not result in an improvement in cognitive performance. Lastly, AÎ²42 immunization resulted in the clearance of amyloid plaques in patients with Alzheimer's disease but did not prevent progressive neurodegeneration.
- Anti-aggregation agents such as apomorphine. These prevent AÎ² fragments from aggregating or clear aggregates once they are formed.
There is some indication that supplementation of the hormone melatonin may be effective against amyloid. Melatonin interacts with amyloid beta and inhibits its aggregation This anti-aggregatory activity occurs only through an interaction with dimers of the soluble amyloid beta peptide. Melatonin does not reverse fibril formation or oligomers of amyloid beta once they are formed. This is supported by experiments in transgenic mice which suggest that melatonin has the potential to prevent amyloid deposition if administered early in life, but it may not be efficacious to revert amyloid deposition or treat Alzheimer's disease.
This connection with melatonin, which regulates sleep, is strengthened by the recent research showing that the wakefulness inducing hormone orexin influences amyloid beta (see below). Interestingly, animal experiments show that melatonin may also correct mild elevations of cholesterol which is also an early risk factor for amyloid formation.
The cannabinoid HU-210 has been shown to prevent amyloid beta-promoted inflammation. The endocannabinoids anandamide and noladin ether have also been shown to be neuroprotective against amyloid beta in vitro.
It has been shown that high-cholesterol diets tend to increase AÎ² pathology in animals. Modulating cholesterol homeostasis has yielded results that show that chronic use of cholesterol-lowering drugs, such as the statins, is associated with a lower incidence of AD. In APP genetically modified mice, cholesterol-lowering drugs have been shown to reduce overall pathology. While the mechanism is poorly understood it appears that cholesterol-lowering drugs have a direct effect on APP processing.
Chelation therapy, which involves the removal of heavy metals from the body, has also been shown to be beneficial in lowering amyloid plaque levels. This is because AÎ² aggregation is somewhat dependent on the metal ions copper and zinc. Zinc in synaptic vesicles, which is under the control of the zinc transporter ZnT3, plays a major role in AÎ² formation. The expression of the ZnT3 is significantly lower in Alzheimerâs patients compared to healthy patients. Mice without ZnT3 were found to have much lower plaque formation. Further promoting this concept, AÎ² deposition was impeded in APP transgenic mice treated with the antibiotic clioquinol, a known copper/zinc chelator.
Drug therapy has been another approach to treatment. Memantine is an Alzheimerâs drug which has received widespread approval. It is a non-competitive N-methyl-D-aspartate (NMDA) channel blocker. By binding to the NMDA receptor with a higher affinity than Mg2+ ions, memantine is able to inhibit the prolonged influx of Ca2+ ions, particularly from extrasynaptic receptors, which forms the basis of neuronal excitotoxicity. It is an option for the management of patients with moderate to severe Alzheimer's Disease (modest effect). The study showed that 20 mg/day improved cognition, functional ability and behavioural symptoms in patient population. Another drug that is currently under research is victoza, which is typically used as a diabetes drug. Treatment with victoza yielded cognitive benefits that included improved object and spatial recognition. Additionally victoza enhances induction and maintenance of long term potentiation (LTP) and paired-pulse facilitation (PPF) in both APP/PS1 and non-genetically altered mice. Other histological benefits include a reduced inflammatory response and an increase in the number of young neurons in the dentate gyrus. The Î²-amyloid level was also found to be significantly reduced.
 Circadian rhythm of amyloid beta
A 2009 report demonstrated that amyloid beta production follows a circadian rhythm, rising when an animal (mouse) or person is awake and falling during sleep. The wakefulness-promoting neuroprotein orexin was shown to be necessary for the circadian rhythm of amyloid beta production. The report suggested that excessive periods of wakefulness (i.e. due to sleep debt) could cause chronic build-up of amyloid beta, which could hypothetically lead to Alzheimer's disease. This is consistent with recent findings that chronic sleep deprivation is associated with early onset Alzheimer's disease.
Melatonin is also involved in circadian rhythm maintenance. Notably, melatonin has been connected with the "sundowning" phenomenon, in which Alzheimer's disease patients that have amyloid plaques in the hypothalamus exhibit exacerbation of Alzheimer's disease symptoms late in the day. This "sundowning" phenomenon could be directly or indirectly related to the recently discovered continuous increase in amyloid beta throughout the day.
 Measuring amyloid beta
There are many different ways to measure Amyloid beta. It can be measured semi-quantitatively with immunostaining, which also allows one to determine location. Amyloid beta may be primarily vascular, as in cerebral amyloid angiopathy, or in senile plaques and vascular.
Imaging compounds, notably Pittsburgh compound B, (6-OH-BTA-1, a thioflavin), can selectively bind to amyloid beta in vitro and in vivo. This technique, combined with PET imaging, has been used to image areas of plaque deposits in Alzheimer's patients.
Dual polarisation interferometry is an optical technique which can measure the very earliest stages of aggregration and inhibition by measuring the molecular size and densities as the fibrils elongate. These aggregate processes can also be studied on lipid bilayer constructs.
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- Strodel B, Lee JW, Whittleston CS, Wales DJ (September 2010). "Transmembrane structures for Alzheimer's AÎ²(1-42) oligomers". J. Am. Chem. Soc. 132 (38): 13300â12. doi:10.1021/ja103725c. PMID 20822103.
- Citron M (September 2004). "Strategies for disease modification in Alzheimer's disease". Nat. Rev. Neurosci. 5 (9): 677â85. doi:10.1038/nrn1495. PMID 15322526.
- Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A (June 2012). "Safety, tolerability, and antibody response of active AÎ² immunotherapy with CAD106 in patients with Alzheimer's disease: randomised, double-blind, placebo-controlled, first-in-human study". Lancet Neurol 11 (7): 597â604. doi:10.1016/S1474-4422(12)70140-0. PMID 22677258. Lay summary â Karolinska Institutet.
- Wang CM, Devries S, Camboni M, Glass M, Martin PT (September 2010). "Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease". Neurobiol. Dis. 39 (3): 409â22. doi:10.1016/j.nbd.2010.05.013. PMC 2913404. PMID 20493257.
- Lashuel HA, Hartley DM, Balakhaneh D, Aggarwal A, Teichberg S, Callaway DJ (November 2002). "New class of inhibitors of amyloid-beta fibril formation. Implications for the mechanism of pathogenesis in Alzheimer's disease". J. Biol. Chem. 277 (45): 42881â90. doi:10.1074/jbc.M206593200. PMID 12167652.
- Parker MH, Chen R, Conway KA, Lee DH, Luo C, Boyd RE, Nortey SO, Ross TM, Scott MK, Reitz AB (November 2002). "Synthesis of (-)-5,8-dihydroxy-3R-methyl-2R-(dipropylamino)-1,2,3,4-tetrahydronaphthalene: an inhibitor of beta-amyloid(1-42) aggregation". Bioorg. Med. Chem. 10 (11): 3565â9. doi:10.1016/S0968-0896(02)00251-1. PMID 12213471.
- Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J (March 1998). "Inhibition of Alzheimer's beta fibrillogenesis by melatonin". J Biol Chem 273 (13): 7185â7188. doi:10.1074/jbc.273.13.7185. PMID 9516407.
- Lahiri DK, Chen DM, Lahiri P, Bondy S, Greig NH (November 2005). "Amyloid, cholinesterase, melatonin, and metals and their roles in aging and neurodegenerative diseases". Ann. N. Y. Acad. Sci. 1056: 430â49. Bibcode:2005NYASA1056..430L. doi:10.1196/annals.1352.008. PMID 16387707.
- Wang XC, Zhang YC, Chatterjie N, Grundke-Iqbal I, Iqbal K, Wang JZ (June 2008). "Effect of melatonin and melatonylvalpromide on beta-amyloid and neurofilaments in N2a cells". Neurochem. Res. 33 (6): 1138â44. doi:10.1007/s11064-007-9563-y. PMID 18231852.
- Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM (November 2009). "Amyloid-Î² Dynamics are Regulated by Orexin and the Sleep-Wake Cycle". Science 326 (5955): 1005â7. Bibcode:2009Sci...326.1005K. doi:10.1126/science.1180962. PMC 2789838. PMID 19779148. Lay summary â News-Medical.Net.
- RamÃrez BG, BlÃ¡zquez C, GÃ³mez del Pulgar T, GuzmÃ¡n M, de Ceballos ML (February 2005). "Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation". J. Neurosci. 25 (8): 1904â13. doi:10.1523/JNEUROSCI.4540-04.2005. PMID 15728830.
- Milton NG (October 2002). "Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide". Neurosci. Lett. 332 (2): 127â30. doi:10.1016/S0304-3940(02)00936-9. PMID 12384227.
- Lee JY, Cole TB, Palmiter RD, Suh SW, Koh JY (May 2002). "Contribution by synaptic zinc to the gender-disparate plaque formation in human Swedish mutant APP transgenic mice". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7705â10. doi:10.1073/pnas.092034699. PMC 124328. PMID 12032347.
- Schneider JS, Pioli EY, Jianzhong Y, Li Q, Bezard E (April 2013). "Effects of memantine and galantamine on cognitive performance in aged rhesus macaques". Neurobiol. Aging 34 (4): 1126â32. doi:10.1016/j.neurobiolaging.2012.10.020. PMID 23158762.
- McClean, P., Parthsarathy, V., Faivre, E., and HÃ¶lscher, C (November 2011). "The Diabetes Drug Liraglutide Prevents Degenerative Processes in a Mouse Model of Alzheimer's Disease". The Journal of Neuroscience 31 (17): 6587â6594. doi:10.1016/S0968-0896(02)00251-1. PMID 12213471.
- Volicer L, Harper D, Manning B, Goldstein R, Satlin A (2001). "Sundowning and circadian rhythms in Alzheimer's disease". Am J Psychiatry 158 (5): 704â11. doi:10.1176/appi.ajp.158.5.704. PMID 11329390.
- Schmidt SD, Nixon RA, Mathews PM (2012). "Tissue processing prior to analysis of Alzheimer's disease associated proteins and metabolites, including AÎ²". Methods Mol. Biol. Methods in Molecular Biology 849: 493â506. doi:10.1007/978-1-61779-551-0_33. ISBN 978-1-61779-550-3. PMID 22528111.
- Schmidt SD, Mazzella MJ, Nixon RA, Mathews PM (2012). "AÎ² measurement by enzyme-linked immunosorbent assay". Methods Mol. Biol. Methods in Molecular Biology 849: 507â527. doi:10.1007/978-1-61779-551-0_34. ISBN 978-1-61779-550-3. PMID 22528112.
- Stine WB, Dahlgren KN, Krafft GA, LaDu MJ (March 2003). "In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis". J. Biol. Chem. 278 (13): 11612â22. doi:10.1074/jbc.M210207200. PMID 12499373.
- Gengler S, Gault VA, Harriott P, HÃ¶lscher C (June 2007). "Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25-35) are dependent on stimulation-protocol and genetic background". Exp Brain Res 179 (4): 621â30. doi:10.1007/s00221-006-0819-6. PMID 17171334.
- Rekas A, Jankova L, Thorn DC, Cappai R, Carver JA (December 2007). "Monitoring the prevention of amyloid fibril formation by alpha-crystallin. Temperature dependence and the nature of the aggregating species". FEBS J. 274 (24): 6290â304. doi:10.1111/j.1742-4658.2007.06144.x. PMID 18005258.
- Sanghera N, Swann MJ, Ronan G, Pinheiro TJ (October 2009). "Insight into early events in the aggregation of the prion protein on lipid membranes". Biochim. Biophys. Acta 1788 (10): 2245â51. doi:10.1016/j.bbamem.2009.08.005. PMID 19703409.
 Further reading
- Martins IC, Kuperstein I, Wilkinson H, Maes E, Vanbrabant M, Jonckheere W, Van Gelder P, Hartmann D, D'Hooge R, De Strooper B, Schymkowitz J, Rousseau F (January 2008). "Lipids revert inert AÎ² amyloid fibrils to neurotoxic protofibrils that affect learning in mice". EMBO J. 27 (1): 224â33. doi:10.1038/sj.emboj.7601953. PMC 2206134. PMID 18059472.
- Istrate AN, Tsvetkov PO, Mantsyzov AB, Kulikova AA, Kozin SA, Makarov AA, Polshakov VI (January 2012). "NMR solution structure of rat AÎ²(1-16): toward understanding the mechanism of rats' resistance to Alzheimer's disease". Biophys J. 102 (1): 136â43. Bibcode:2012BpJ...102..136I. doi:10.1016/j.bpj.2011.11.4006. PMC 3250693. PMID 22225807.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Beta-amyloid peptide (beta-APP) Provide feedback
No Pfam abstract.
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR013803
Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques [PUBMED:16301322, PUBMED:16364896]. Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.
APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products [PUBMED:16406235]. APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility [PUBMED:16406235]. APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death [PUBMED:12611883]. The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.
APP can be processed by different sets of enzymes:
- In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).
- In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.
This entry represents the amyloid-beta peptide (A-beta), which originates as a breakdown product from the cleavage of amyloid-beta precursor protein (APP, or A4), an integral, glycosylated membrane brain protein.
More information about these protein can be found at Protein of the Month: Amyloid-beta Precursor Protein [PUBMED:].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||integral to membrane (GO:0016021)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the NCBI sequence database using the family HMM
- alignment generated by searching the metagenomics sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
- Pfam viewer
- an HTML-based viewer that uses DAS to retrieve alignment fragments on request
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Number in seed:||2|
|Number in full:||171|
|Average length of the domain:||38.90 aa|
|Average identity of full alignment:||89 %|
|Average coverage of the sequence by the domain:||6.25 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||8|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There is 1 interaction for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Beta-APP domain has been found. There are 133 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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