Solution Conformation and Heparin-induced Dimerization of the Full-length Extracellular Domain of the Human Amyloid Precursor Protein

Gralle, Matthias; Oliveira, C. L. P.; Guerreiro, Luiz Henrique; McKinstry, William J.; Galatis, Denise; Masters, Colin L.; Cappai, Roberto; Parker, Michael W.; Ramos, Carlos H.I.; Torriani, Íris L.; Ferreira, Sérgio T.

doi:10.1016/j.jmb.2005.12.053

Cited by 65 publications

(85 citation statements)

References 62 publications

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“…The successful structural investigation and its binding to heparin show that the protein is of native fold and no glycosylation sites that possibly could interfere with ligand binding are known within the E1 domain. Unlike previously assumed, the two constituting subdomains GFLD and CuBD interact tightly, showing an overall arrangement different from those predicted from SAXS and modeling analyses (16,38). Despite the rather small interface area (496 Å 2 ), the two subdomains form a stable unit in the crystal lattice, confirmed by low B factors of the interface residues, and in solution (evidenced by our limited proteolysis experiments).…”

Section: Discussioncontrasting

confidence: 71%

“…A linker of unknown structure containing the α-and β-secretase cleavage sites connects the ectodomain to a helical transmembrane segment containing the γ-secretase cleavage site, which is followed by a short cytoplasmic domain (AICD) of weak secondary structure (15). Integration of the structural information on isolated fragments into a comprehensive overall picture has been attempted by small angle x-ray scattering (SAXS) (16). However, the resulting SAXS model has not been corroborated by other structural or functional studies to date.…”

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confidence: 99%

“…In addition to monomeric protein, dimers and higher oligomers are found for both isolated subdomains and full length APP (13,16,28). The ordered dimerization of APP has also been implicated in cell-cell interactions (29).…”

mentioning

confidence: 99%

“…The ordered dimerization of APP has also been implicated in cell-cell interactions (29). It has been reported that dimerization depends on zinc binding (18,30), heparin binding (16), or the simultaneous interaction of several sites within the APP molecule (31) including its transmembrane domain (29) and that it is functionally associated with the concurrent dimerization of the β-site APP cleaving enzyme (28,(31)(32)(33). Recently, Gralle et al corroborated the physiological importance of APP dimerization using single molecule FRET methods (27).…”

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confidence: 99%

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Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

Dahms

Hoefgen

Roeser

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

106

128

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The authors note the following: "Due to an error in the evaluation of the raw ITC-data, we reported the wrong sign for the enthalpy values and correspondingly incorrect entropy values. The correct values are as follows: at pH 5.7: ΔH −54 ± 4 kJ/ mol, ΔS −68 ± 14 J/mol K and at pH 7.2: ΔH −62 ± 6 kJ/mol and ΔS −98 ± 18 J/mol K (Table 3)." The authors note that on page 5381, left column, first paragraph, line 9 "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an endothermic and pH-dependent process that is characterized by a low micromolar dissociation constant" should have read "Two E1 entities dimerize upon their interaction with heparin, requiring 8-12 sugar rings to form the heparin-bridged APP-E1 dimer in an exothermic and pH-dependent process that is characterized by a low micromolar dissociation constant." On page 5384, right column, third paragraph, line 23 "This reaction is driven by high entropy contributions of around 300 J/mol · K, probably resulting from the release of associated ions and water molecules upon heparin binding, as also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)" should have read "This reaction is driven by significant enthalpic contributions, probably arising from protein-protein interactions, also observed for other heparin-binding proteins (reviewed, e.g., in ref. 39)." This error does not affect the conclusions of the article.

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Section: Discussioncontrasting

confidence: 71%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

Dahms

Hoefgen

Roeser

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

106

128

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“…For example, neurite outgrowth is stimulated by cell-cell adhesion involving cell surface-expressed APP; cellular substrata displaying APP isoforms that possess the Kunitz domain are most effective at promoting neurite outgrowth (68). Furthermore, structural models of intact APP 770 place the Kunitz domain in a fully exposed position on the side of the ectodomain farthest from the membrane attachment point (69). Thus, it is plausible that intermolecular interactions involving the Kunitz domain may impact some of the adhesion properties of cell surface APP and that cleavage of the Kunitz domain by mesotrypsin could impact these properties as well.…”

Section: Discussionmentioning

confidence: 99%

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Salameh

Robinson

Navaneetham

et al. 2010

Journal of Biological Chemistry

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The amyloid precursor protein (APP) is a ubiquitously expressed transmembrane adhesion protein and the progenitor of amyloid-␤ peptides. The major splice isoforms of APP expressed by most tissues contain a Kunitz protease inhibitor domain; secreted APP containing this domain is also known as protease nexin 2 and potently inhibits serine proteases, including trypsin and coagulation factors. The atypical human trypsin isoform mesotrypsin is resistant to inhibition by most protein protease inhibitors and cleaves some inhibitors at a substantially accelerated rate. Here, in a proteomic screen to identify potential physiological substrates of mesotrypsin, we find that APP/protease nexin 2 is selectively cleaved by mesotrypsin within the Kunitz protease inhibitor domain. In studies employing the recombinant Kunitz domain of APP (APPI), we show that mesotrypsin cleaves selectively at the Arg 15 -Ala 16 reactive site bond, with kinetic constants approaching those of other proteases toward highly specific protein substrates. Finally, we show that cleavage of APPI compromises its inhibition of other serine proteases, including cationic trypsin and factor XIa, by 2 orders of magnitude. Because APP/protease nexin 2 and mesotrypsin are coexpressed in a number of tissues, we suggest that processing by mesotrypsin may ablate the protease inhibitory function of APP/protease nexin 2 in vivo and may also modulate other activities of APP/protease nexin 2 that involve the Kunitz domain.Mesotrypsin is a human trypsin encoded by the PRSS3 gene found on chromosome 9p13 (1). Normal expression of PRSS3 is restricted to pancreas, brain, and, to a lesser extent, small intestine and colon (2-4); additionally, PRSS3 appears to be transcriptionally up-regulated with cancer progression in epithelial cancers, including lung (5), colon (6), and prostate. Mesotrypsin exhibits substantially different specificity from other trypsins toward protein substrates. It fails to activate pancreatic zymogens and also shows reduced capacity to degrade trypsinogens (7). Compared with other trypsins, it is significantly compromised in its ability to cleave protease-activated receptors (8 -10). Despite limited activity toward these classic trypsin substrates, mesotrypsin displays enhanced catalytic activity compared with other trypsins in the cleavage of certain specific protein substrates, most notably several canonical protease inhibitors (7, 11).The "canonical" inhibitors of serine proteases, named for a protease-binding loop of highly characteristic backbone conformation (12, 13), fulfill the paradoxical function of binding to a protease in a substrate-like manner yet acting as an inhibitor rather than an ordinary substrate. These inhibitors, representing at least 18 different convergently evolved protein families (14, 15), inhibit their cognate proteases via the "Laskowski mechanism," in which inhibitors act as highly specific, limited proteolysis substrates for target enzymes (14, 16). They bind so as to position a specific peptide bond, the "reactive si...

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Amyloid Precursor Protein

Leong

Barnham

Multhaup

et al. 2004

Handbook of Metalloproteins

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The amyloid‐precursor protein (APP) is a transmembrane glycoprotein implicated in the pathogenesis of Alzheimer's disease (AD). In mammals, there are two paralogues of APP termed amyloid precursor‐like protein 1 (APLP1) and amyloid precursor‐like protein 2 (APLP2). Orthologues of APP also exist, suggesting a conserved function vital throughout evolution. APP is a multidomain protein with metal‐binding sites critical to its function. There are two copper‐binding domains, one lies in the N‐terminus, adjacent to the zinc‐binding domain, and the other is in the amyloid‐beta (Aβ) domain. Aβ is derived via a series of protease cleavages of APP by the secretases, and is the main constituent of the amyloid plaques that are a key pathological hallmark of AD. The physiological role of APP is as yet unknown. It can reduce Cu 2+ to Cu + , and the physiological and three‐dimensional structure suggests a role as a copper chaperone. The binding of Cu to Aβ is toxic to neuronal cultures, and this may contribute to the oxidative stress that is commonly observed in AD.

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Solution Conformation and Heparin-induced Dimerization of the Full-length Extracellular Domain of the Human Amyloid Precursor Protein

Cited by 65 publications

References 62 publications

Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein

The Amyloid Precursor Protein/Protease Nexin 2 Kunitz Inhibitor Domain Is a Highly Specific Substrate of Mesotrypsin

Amyloid Precursor Protein

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