X11L2, a New Member of the X11 Protein Family, Interacts with Alzheimer's β-Amyloid Precursor Protein

Tanahashi, Hiroshi; Tabira, Takeshi

doi:10.1006/bbrc.1999.0265

Cited by 73 publications

(48 citation statements)

References 18 publications

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“…Mint3 is a member of the X11 family of proteins that bind APP via a C-terminal conserved domain (15,25). It is reported to localize to the Golgi complex and is implicated in vesicle transport (15,18,(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

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Mint3 Enhances the Activity of Hypoxia-inducible Factor-1 (HIF-1) in Macrophages by Suppressing the Activity of Factor Inhibiting HIF-1

Sakamoto

Seiki

2009

Journal of Biological Chemistry

101

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Hypoxia-inducible factor-1 (HIF-1) is a key transcription factor regulating cellular responses to hypoxia and is composed of ␣ and ␤ subunits. During normoxia, factor inhibiting HIF-1 (FIH-1) inhibits the activity of HIF-1 by preventing HIF-1␣ binding to p300/CBP via modification of the Asn 803 residue. However, it is not known whether FIH-1 activity can be regulated in an oxygen-independent manner. In this study, we survey possible binding proteins to FIH-1 and identify Mint3/APBA3, which has been reported to bind Alzheimer ␤-amyloid precursor protein. Purified Mint3 binds FIH-1 and inhibits the ability of FIH-1 to modify HIF-1␣ in vitro. In a reporter assay, the activity of HIF-1␣ is suppressed because of endogenous FIH-1 in HEK293 cells, and expression of Mint3 antagonizes this suppression. Macrophages are known to depend on glycolysis for ATP production because of elevated HIF-1 activity. FIH-1 activity is suppressed in macrophages by Mint3 so as to maintain HIF-1 activity. FIH-1 forms a complex with Mint3, and these two factors co-localize within the perinuclear region. Knockdown of Mint3 expression in macrophages leads to redistribution of FIH-1 to the cytoplasm and decreases glycolysis and ATP production. Thus, Mint3 regulates the FIH-1-HIF-1 pathway, which controls ATP production in macrophages and therefore represents a potential new therapeutic target to regulate macrophage-mediated inflammation.

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Section: Discussionmentioning

confidence: 99%

“…Mint3 Competes with HIF-1␣ for Binding to FIH-1-Mint3 is a member of the X11 protein family (15,16). The C-terminal half of Mint3 contains one phosphotyrosine-binding and two PDZ domains ( Fig.…”

Section: Identification Of Mint3 As a New Binding Partner Of Fih-1-mentioning

confidence: 99%

Mint3 Enhances the Activity of Hypoxia-inducible Factor-1 (HIF-1) in Macrophages by Suppressing the Activity of Factor Inhibiting HIF-1

Sakamoto

Seiki

2009

Journal of Biological Chemistry

101

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“…Such sorting motifs function by binding specific adaptors to facilitate their selective import into budding carriers and ensure specificity in cargo selection and coat recruitment. The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al, 1996(Borg et al, , 1998Zhang et al, 1997;Sastre et al, 1998;Tanahashi and Tabira, 1999;Tomita et al, 1999;Ho et al, 2002;Araki et al, 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al, 1999) family, Dab2 (Howell et al, 1999), JIP1b (King et al, 2004), and ARH (Noviello et al, 2003).…”

Section: Introductionmentioning

confidence: 97%

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Shrivastava-Ranjan

Faúndez

Fang

et al. 2008

MBoC

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␤-Amyloid peptides (A␤) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the ␤-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic ␤-amyloid peptide, A␤ 1-40 . Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic. INTRODUCTIONThe hallmark of Alzheimer's disease is the presence in brain of plaques that contain A␤ peptides, formed by the result of proteolytic processing of the ␤-amyloid precursor protein (APP). APP is a ubiquitous, single-pass transmembrane protein of unknown function that is highly expressed in brain. Processing involves the sequential actions of ␣-or ␤-plus ␥-secretases, each of which are found in multiple cellular locations (Kuentzel et al., 1993;Selkoe, 1998;Yan et al., 2001). Although processing may occur at any step, the trans-Golgi network (TGN) is the earliest site at which APP processing is thought to commence, and APP is internalized from the cell surface to endosomal compartments where ␥-secretase also acts (Selkoe et al., 1996;Greenfield et al., 1999;Lah and Levey, 2000;Bagshaw et al., 2003).The C-terminal domain of APP contains the tyrosinebased sorting motif, YENPTY, which is conserved across species and a determinant of APP traffic (Perez et al., 1999;Bonifacino and Traub, 2003;King et al., 2004). Such sorting motifs function by binding specific adaptors to facilitate their selective import into budding carriers and ensure specificity in cargo selection and coat recruitment. The highly conserved phosphotyrosine binding (PTB) domains in all three Mint proteins have been shown previously to bind directly to the YENPXY motif of APP (Borg et al., 1996(Borg et al., , 1998Zhang et al., 1997;Sastre et al., 1998;Tanahashi and Tabira, 1999;Tomita et al., 1999;Ho et al., 2002;Araki et al., 2003). Other PTB domain containing proteins have similarly been shown to bind APP, including the Fe65 (Sabo et al., 1999) family, Dab2 (Howell et al., 1999), JIP1b (King et al....

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“…Mints consist of a divergent N-terminal region and conserved C-terminal sequences composed of a phosphotyrosine binding (PTB) domain and two tandem PDZ (postsynaptic density-95/discs large/zona occludens-1) domains. The PTB domain of all Mints interacts directly with a conserved YENPTY cytoplasmic motif of the APP that is essential for regulating APP trafficking and processing (3)(4)(5)(6). APP is a type I transmembrane protein that is sequentially cleaved by site-specific proteases (7)(8)(9)(10).…”

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confidence: 99%

Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing

Matos

Xu²,

Dulubova

et al. 2012

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

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Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer's disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PTB fragment reveals that the linker region forms a short α-helix that folds back onto the PTB domain and sterically hinders APP binding. This intramolecular interaction is disrupted by mutation of Tyr633 within the Mint1 autoinhibitory helix leading to enhanced APP binding and β-amyloid production. Our findings suggest that an autoinhibitory mechanism in Mint1 is important for regulating APP processing and may provide novel therapies for Alzheimer's disease.M ints [also known as X11s or amyloid precursor protein (APP) binding, family A] are a family of adaptor proteins encoded by three genes: neuron-specific Mint1 and Mint2, and the ubiquitously expressed Mint3 (1, 2). Mints consist of a divergent N-terminal region and conserved C-terminal sequences composed of a phosphotyrosine binding (PTB) domain and two tandem PDZ (postsynaptic density-95/discs large/zona occludens-1) domains. The PTB domain of all Mints interacts directly with a conserved YENPTY cytoplasmic motif of the APP that is essential for regulating APP trafficking and processing (3-6). APP is a type I transmembrane protein that is sequentially cleaved by site-specific proteases (7-10). Abnormal processing of APP generates Aβ peptides leading to the accumulation of extracellular plaques that are characteristic of Alzheimer's disease (AD). β-Secretase is the first amyloidogenic cleavage, generating a soluble APP ectodomain (sAPPβ) and a C-terminal fragment (CTFβ). CTFβ is subsequently cleaved by γ-secretase (a protein complex of anterior pharyx defective 1, nicastrin, presenilin, and presenilin enhancer 2) to release the small peptides Aβ40 and Aβ42, the latter having an increased propensity to form amyloid aggregates found in the brains of AD patients (11)(12)(13)(14). Alternatively, APP is sequentially cleaved by α-secretase within the Aβ region then γ-secretase, which initiates the nonamyloidogenic or nontoxic pathway (9, 10).Considerable evidence indicates that the APP-Mint interaction is biologically significant because loss of each individual Mint protein delays age-dependent production of amyloid plaques in transgenic AD mouse models (15). Past studies have indicated that the N-and C-terminal regions of Mints play an important role in regulating APP binding and cleavage events based on deletion analysis of Mints in a heterologous expression system (6, 16). The Mint N terminus was shown to promote APP binding and Aβ production, whereas the C-terminal region disrupted PTB-mediated binding to APP and decreased Aβ peptides (6, 16). However, the structural basis ...

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X11L2, a New Member of the X11 Protein Family, Interacts with Alzheimer's β-Amyloid Precursor Protein

Cited by 73 publications

References 18 publications

Mint3 Enhances the Activity of Hypoxia-inducible Factor-1 (HIF-1) in Macrophages by Suppressing the Activity of Factor Inhibiting HIF-1

Mint3 Enhances the Activity of Hypoxia-inducible Factor-1 (HIF-1) in Macrophages by Suppressing the Activity of Factor Inhibiting HIF-1

Mint3/X11γ Is an ADP-Ribosylation Factor-dependent Adaptor that Regulates the Traffic of the Alzheimer's Precursor Protein from theTrans-Golgi Network

Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing

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