Calsyntenin-1, a Proteolytically Processed Postsynaptic Membrane Protein with a Cytoplasmic Calcium-Binding Domain

Vogt, Lorenz; Schrimpf, Sabine; Meskenaïte, Virginia; Frischknecht, Renato; Kinter, Jochen; Leone, Dino P.; Ziegler, Urs; Sonderegger, P.

doi:10.1006/mcne.2000.0937

Cited by 98 publications

(126 citation statements)

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“…Alcs are type I membrane proteins, as is APP, and a previous report has suggested that the Alc/ calsyntenin proteins are cleaved extracellularly (10). These observations led us to speculate that the Alcs are metabolized in a similar manner to APP.…”

Section: Alcs Are Metabolized In a Similar Manner To App And Arementioning

confidence: 84%

“…During our previous research that aimed to reveal the molecular mechanism by which X11L regulates APP metabolism, we found that the Alcadeins, which form cadherin-related membrane protein family, are X11-and X11L-binding proteins (9). These proteins are also known as calsyntenins, which were originally isolated as postsynaptic Ca 2ϩ -binding membrane proteins, but whose functions were not identified (10,11). The Alcadeins (Alcs) consist of two Alc␣ isoforms (Alc␣1 and Alc␣2) and Alc␤ and Alc␥, all of which are type I transmembrane proteins and contain a conserved X11L-binding motif in their single cytoplasmic domains, similar to APP (9).…”

mentioning

confidence: 99%

“…The Alc-X11L-CTF␤ complex promotes the X11L-dependent inhibition of the ␥-secretase cleavage of the CTF␤ because the complexing of CTF␤ interferes with its interaction with presenilin (PS) (9). Moreover, it has been shown that APP and Alc co-localize in neurons (9) and that calsyntenin-1 is extracellularly cleaved (10). This suggests that APP and Alc may be metabolized in a coordinated fashion by a secretase(s).…”

mentioning

confidence: 99%

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Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

Araki

Miyagi

Kato

et al. 2004

Journal of Biological Chemistry

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The Alcadeins (Alcs)/calsyntenins and the amyloid ␤-protein precursor (APP) associate with each other in the brain by binding via their cytoplasmic domains to X11L (the X11-like protein). We previously reported that the formation of this APP-X11L-Alc tripartite complex suppresses the metabolic cleavages of APP. We show here that the metabolism of the Alcs markedly resembles that of APP. The Alcs are subjected to a primary cleavage event that releases their extracellular domain. Alcs then undergo a secondary presenilin-dependent ␥-cleavage that leads to the secretion of the amyloid ␤-protein-like peptide and the liberation of an intracellular domain fragment (AlcICD). However, when Alc is in the tripartite complex, it escapes from these cleavages, as does APP. We also found that AlcICD suppressed the FE65-dependent gene transactivation activity of the APP intracellular domain fragment, probably because AlcICD competes with the APP intracellular domain fragment for binding to FE65. We propose that the Alcs and APP are coordinately metabolized in neurons and that their cleaved cytoplasmic fragments are reciprocally involved in the regulation of FE65-dependent gene transactivation. Any imbalance in the metabolism of Alcs and APP may influence the FE65-dependent gene transactivation, which together with increased secretion of amyloid ␤-protein may contribute to neural disorders.The deposition and accumulation of amyloid ␤-protein (A␤) 1 in the human brain are hallmarks of Alzheimer's disease (AD)(1). Amyloid ␤-protein precursor (APP) is the precursor of A␤. It has a receptor-like transmembrane protein structure that consists of an extracellular domain, a transmembrane domain, and a short carboxyl-terminal cytoplasmic domain (2). The cytoplasmic domain of APP controls its metabolism and various physiological functions by interacting with cytoplasmic adaptor proteins (3-8). One of these adaptor proteins is X11L (the X11-like protein), which associates with the cytoplasmic domain of APP and stabilizes APP metabolism (5, 9). During our previous research that aimed to reveal the molecular mechanism by which X11L regulates APP metabolism, we found that the Alcadeins, which form cadherin-related membrane protein family, are X11-and X11L-binding proteins (9). These proteins are also known as calsyntenins, which were originally isolated as postsynaptic Ca 2ϩ -binding membrane proteins, but whose functions were not identified (10, 11). The Alcadeins (Alcs) consist of two Alc␣ isoforms (Alc␣1 and Alc␣2) and Alc␤ and Alc␥, all of which are type I transmembrane proteins and contain a conserved X11L-binding motif in their single cytoplasmic domains, similar to APP (9).Alc does not directly interact with the cytoplasmic domain of APP. Rather, the association between the two molecules is bridged by the phosphotyrosine interaction domain of X11L. This results in the formation of a tripartite complex in the brain (9). The formation of this complex enhances the X11L-mediated stabilization of APP metabolism and suppresses the generation...

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Section: Alcs Are Metabolized In a Similar Manner To App And Arementioning

confidence: 84%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

Araki

Miyagi

Kato

et al. 2004

Journal of Biological Chemistry

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“…Calsyntenins (also called alcadeins or Alcs) are cadherin-like type I transmembrane proteins originally found in mammals. They are highly expressed in the central nervous system (13,14). Biochemical studies revealed that calsyntenins/alcadeins can associate with the scaffold protein X11/X11L, which in turn associates with APP, resulting in the formation of a tripartite complex in the brain (15).…”

mentioning

confidence: 99%

“…Calsyntenins and APP are coordinately metabolized in neurons (16). The extracellular region of calsyntenin-1 is released into the synaptic cleft, whereas the intracellular region, which can bind Ca 2ϩ , is internalized (13,16). Furthermore, interaction between calsyntenin-1 and kinesin-1 blocked transport of APP-containing vesicles and increased ␤-amyloid generation (17).…”

mentioning

confidence: 99%

CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans

Ikeda

Duan

Matsuki

et al. 2008

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

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Calsyntenins/alcadeins are type I transmembrane proteins with two extracellular cadherin domains highly expressed in mammalian brain. They form a tripartite complex with X11/X11L and APP (amyloid precursor protein) and are proteolytically processed in a similar fashion to APP. Although a genetic association of calsyntenin-2 with human memory performance has recently been reported, physiological roles and molecular functions of the protein in the nervous system are poorly understood. Here, we show that CASY-1, the Caenorhabditis elegans ortholog of calsyntenins/ alcadeins, is essential for multiple types of learning. Through a genetic screen, we found that casy-1 mutants show defects in salt chemotaxis learning. casy-1 mutants also show defects in temperature learning, olfactory adaptation, and integration of two sensory signals. casy-1 is widely expressed in the nervous system. Expression of casy-1 in a single sensory neuron and at the postdevelopmental stage is sufficient for its function in salt chemotaxis learning. The fluorescent protein-tagged ectodomain of CASY-1 is released from neurons. Moreover, functional domain analyses revealed that both cytoplasmic and transmembrane domains of this protein are dispensable, whereas the ectodomain, which contains the LG/LNS-like domain, is critically required for learning. These results suggest that learning is modulated by the released ectodomain of CASY-1.ectodomain shedding ͉ learning and memory

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Alzheimer's Disease as a Membrane‐Associated Enzymopathy of β‐Amyloid Precursor Protein (APP) Secretases

Hata

Saito

Suzuki

2011

Lipids and Cellular Membranes in Amyloid Diseases

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Calsyntenin-1, a Proteolytically Processed Postsynaptic Membrane Protein with a Cytoplasmic Calcium-Binding Domain

Cited by 98 publications

References 49 publications

Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

Coordinated Metabolism of Alcadein and Amyloid β-Protein Precursor Regulates FE65-dependent Gene Transactivation

CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans

Alzheimer's Disease as a Membrane‐Associated Enzymopathy of β‐Amyloid Precursor Protein (APP) Secretases

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