Amyloid precursor protein

Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease)
PDB rendering based on 1aap.
Available structures
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
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
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	351	11820
Ensembl	ENSG00000142192	ENSMUSG00000022892
UniProt	P05067	Q8BPC7
RefSeq	NM_000484 (mRNA)	NM_007471 (mRNA)
	NP_000475 (protein)	NP_031497 (protein)
Location	Chr 21: 26.17 - 26.47 Mb	Chr 16: 84.84 - 85.06 Mb
PubMed search	[1]	[2]

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.^[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 and most commonly studied as the precursor molecule whose proteolysis generates amyloid beta (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.^[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; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease.^[6] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals.^[7] 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.^[7]

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.^[8][9][10] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ.^[11]

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.^[12] 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 as well as a zinc-binding domain in multiple configurations and ion-binding states^[13] and the E2 dimerization 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.^[14] 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.^[7] 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.^[15]

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.^[16] Gamma secretase activity has also been associated with lipid rafts.^[17] 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.^[18]

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. 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.^[7] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch.^[19] APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss.^[20] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation.^[21] 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.^[22] 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 effect physiological deficits that contribute to dementia.

Interactions

Amyloid precursor protein has been shown to interact with APBA3,^[23][24] CLSTN1,^[25][26] APPBP1,^[27] Gelsolin,^[28] BCAP31,^[29] Caveolin 1,^[30] FBLN1,^[31] Collagen, type XXV, alpha 1,^[32] APBB1,^{[33][34][35][36][37]} APBA2,^[23][26][38] APBA1,^[23][33] APPBP2,^[39] HSD17B10,^[40] BLMH^[41] and SHC1.^[42]

One groups of scientists reports that APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease.^[43]

References

Further reading

v • d • e PDB Gallery 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)

External links

Wikimedia Commons has media related to: APP

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