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31-1395: 1AAP , 1AMB , 1AMC , 1AML , 1BA4 , 1BA6 , 1BJB , 1BJC , 1BRC , 1CA0 , 1HZ3 , 1IYT , 1MWP , 1OWT , 1QCM , 1QWP , 1QXC , 1QYT , 1TAW , 1TKN , 1X11 , 1Z0Q , 1ZJD , 2BEG , 2BP4 , 2FJZ , 2FK1 , 2FK2 , 2FK3 , 2FKL , 2FMA , 2G47 , 2IPU , 2LFM , 2LLM , 2LMN , 2LMO , 2LMP , 2LMQ , 2LOH , 2LP1 , 2OTK , 2R0W , 2WK3 , 2Y29 , 2Y2A , 2Y3J , 2Y3K , 2Y3L , 3AYU , 3DXC , 3DXD , 3DXE , 3GCI , 3IFL , 3IFN , 3IFO , 3IFP , 3JTI , 3KTM , 3L33 , 3L81 , 3MOQ , 3NYL , 3SV1 , 3U0T , 3UMH , 3UMI , 3UMK , 4HIX , 1ZE7 , 1ZE9 , 2LNQ , 2LZ3 , 2LZ4 , 2M4J , 2M9R , 2M9S , 2MGT , 2MJ1 , 2MPZ , 2MVX , 2MXU , 3BAE , 3BKJ , 3JQ5 , 3JQL , 3MXC , 3NYJ , 3OVJ , 3OW9 , 4JFN , 4M1C , 4MDR , 4NGE , 4OJF , 4ONF , 4ONG , 4PQD , 4PWQ , 4MVI , 4MVK , 4MVL , 4XXD , 5CSZ , 5AMB , 5AEF , 5AM8 , 5BUO , 5HOY , 5HOW , 5HOX , 5KK3 , 5C67 , 2NAO 351 11820 ENSG00000142192 ENSMUSG00000022892 P05067 P12023 NM_001136131 NM_001204301 NM_001204302 NM_001204303 NM_201413 NM_001385253 NM_001198823 NM_001198824 NM_001198825 NM_001198826 NM_007471 NP_001191230 NP_001191231 NP_001191232 NP_958816 NP_958817 NP_001185752 NP_001185753 NP_001185754 NP_001185755 NP_031497 Amyloid-beta precursor protein ( APP )

62-574: 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. Amyloid-beta precursor protein is an ancient and highly conserved protein . In humans , the gene APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases . 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

93-567: A single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation. 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. 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

124-598: A 40% reduction in the formation of amyloid beta in vitro. 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. A serine protease inhibitor domain, absent from

155-436: A channel through the membrane. Type V proteins are anchored to the lipid bilayer through covalently linked lipids. Finally Type VI proteins have both transmembrane domains and lipid anchors. Integral monotopic proteins are associated with the membrane from one side but do not span the lipid bilayer completely. Many challenges facing the study of integral membrane proteins are attributed to the extraction of those proteins from

186-448: A decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia. In neurons of the human brain , somatic recombination occurs frequently in the gene that encodes APP. Neurons from individuals with sporadic Alzheimer's disease show greater APP gene diversity due to somatic recombination than neurons from healthy individuals. Molecules synthesized in

217-500: A likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease. 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. The most-substantiated role for APP

248-509: 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

279-566: A related homologous protein. This procedure has been extensively used for ligand - G protein–coupled receptors (GPCR) and their complexes. IMPs include transporters , linkers, channels , receptors , enzymes , structural membrane-anchoring domains, proteins involved in accumulation and transduction of energy , and proteins responsible for cell adhesion . Classification of transporters can be found in Transporter Classification Database . As an example of

310-451: Is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons . It functions as a cell surface receptor and has been implicated as a regulator of synapse formation , neural plasticity , antimicrobial activity, and iron export . It is coded for by the gene APP and regulated by substrate presentation . APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ),

341-635: 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

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372-428: 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. 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

403-521: The Protein Data Bank . Their membrane-anchoring α-helices have been removed to facilitate the extraction and crystallization . Search integral membrane proteins in the PDB (based on gene ontology classification) IMPs can be divided into two groups: The most common type of IMP is the transmembrane protein , which spans the entire biological membrane . Single-pass membrane proteins cross

434-568: The phospholipid bilayer . Since integral proteins span the width of the phospholipid bilayer, their extraction involves disrupting the phospholipids surrounding them, without causing any damage that would interrupt the function or structure of the proteins. Several successful methods are available for performing the extraction including the uses of "detergents, low ionic salt (salting out), shearing force, and rapid pressure change". The Protein Structure Initiative (PSI), funded by

465-532: The U.S. National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health (NIH), has among its aim to determine three-dimensional protein structures and to develop techniques for use in structural biology , including for membrane proteins. Homology modeling can be used to construct an atomic-resolution model of the "target" integral protein from its amino acid sequence and an experimental three-dimensional structure of

496-428: 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. Additionally, it has been shown that

527-486: The cell cycle. 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. Integral membrane protein Proteins that adhere only temporarily to cellular membranes are known as peripheral membrane proteins . These proteins can either associate with integral membrane proteins, or independently insert in

558-469: 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 and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC. AβPP and its cleavage products do not promote

589-428: 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 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

620-418: The interaction between APP and kinesin is specific to the peptide sequence of APP. 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

651-435: 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 ). 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

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682-584: 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. 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

713-458: The isoform diversity of APP is essential for deciphering its various physiological and pathological roles. 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. It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly

744-438: The lipid bilayer in several ways. Three-dimensional structures of ~160 different integral membrane proteins have been determined at atomic resolution by X-ray crystallography or nuclear magnetic resonance spectroscopy . They are challenging subjects for study owing to the difficulties associated with extraction and crystallization . In addition, structures of many water - soluble protein domains of IMPs are available in

775-479: The membrane only once, while multi-pass membrane proteins weave in and out, crossing the membrane several times. Single pass membrane proteins can be categorized as Type I, which are positioned such that their carboxyl-terminus is towards the cytosol , or Type II, which have their amino-terminus towards the cytosol. Type III proteins have multiple transmembrane domains in a single polypeptide, while type IV consists of several different polypeptides assembled together in

806-499: 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

837-479: 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 indicate that this deficit in APP results from

868-477: 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 . 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 and re-entry of post-mitotic neurons into

899-451: The region that generates amyloid beta (Aβ), 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. 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

930-490: The relationship between the IMP (in this case the bacterial phototrapping pigment, bacteriorhodopsin) and the membrane formed by the phospholipid bilayer is illustrated below. In this case the integral membrane protein spans the phospholipid bilayer seven times. The part of the protein that is embedded in the hydrophobic regions of the bilayer are alpha helical and composed of predominantly hydrophobic amino acids. The C terminal end of

961-413: The terminal COOH moiety of peptides is not sufficient to mediate transport. 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. It has been shown that

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