The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2

Beckmann, Anna-Madeleine; Glebov, Konstantin; Walter, Jochen; Merkel, Olaf; Mangold, Martin; Schmidt, Frederike; Becker‐Pauly, Christoph; Gütschow, Michael; Stirnberg, Marit

doi:10.1515/hsz-2015-0263

Cited by 10 publications

(8 citation statements)

References 40 publications

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“…Two examples are shown in Figure 6D. Alternative splicing of Amyloid precursor-like protein 2 ( Aplp2 ) is known to regulate inclusion of a bovine pancreatic trypsin inhibitor (BPTI) Kunitz domain (Sandbrink et al, 1997) and this domain is known to regulate proteolysis of the related protein APP, the amyloid precursor protein implicated in Alzheimer’s disease (Beckmann et al, 2016). Differential inclusion of this exon is known to occur between neurons and nonneurons.…”

Section: Resultsmentioning

confidence: 99%

Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain

Sugino

Clark

Schulmann

et al. 2019

eLife

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Understanding the principles governing neuronal diversity is a fundamental goal for neuroscience. Here, we provide an anatomical and transcriptomic database of nearly 200 genetically identified cell populations. By separately analyzing the robustness and pattern of expression differences across these cell populations, we identify two gene classes contributing distinctly to neuronal diversity. Short homeobox transcription factors distinguish neuronal populations combinatorially, and exhibit extremely low transcriptional noise, enabling highly robust expression differences. Long neuronal effector genes, such as channels and cell adhesion molecules, contribute disproportionately to neuronal diversity, based on their patterns rather than robustness of expression differences. By linking transcriptional identity to genetic strains and anatomical atlases, we provide an extensive resource for further investigation of mouse neuronal cell types.

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Section: Resultsmentioning

confidence: 99%

Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain

Sugino

Clark

Schulmann

et al. 2019

eLife

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“…Matriptase‐2 is a member of the type II transmembrane serine proteases (TTSPs), an understudied group of 17 membrane‐bound serine proteases (Szabo & Bugge, ), and has been reported to shed APP within the amyloid β domain, at least in transfected cells or in vitro (Beckmann et al , ). Other TTSPs appear to cleave predominantly soluble proteins or activate membrane‐bound proteins, but without shedding them in their juxtamembrane domains (Jackle et al , ; Murray et al , ).…”

Section: Hardware: Canonical Sheddasesmentioning

confidence: 99%

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

2018

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Proteolytic removal of membrane protein ectodomains (ectodomain shedding) is a post-translational modification that controls levels and function of hundreds of membrane proteins. The contributing proteases, referred to as sheddases, act as important molecular switches in processes ranging from signaling to cell adhesion. When deregulated, ectodomain shedding is linked to pathologies such as inflammation and Alzheimer's disease. While proteases of the "a disintegrin and metalloprotease" (ADAM) and "beta-site APP cleaving enzyme" (BACE) families are widely considered as sheddases, in recent years a much broader range of proteases, including intramembrane and soluble proteases, were shown to catalyze similar cleavage reactions. This review demonstrates that shedding is a fundamental process in cell biology and discusses the current understanding of sheddases and their substrates, molecular mechanisms and cellular localizations, as well as physiological functions of protein ectodomain shedding. Moreover, we provide an operational definition of shedding and highlight recent conceptual advances in the field. While new developments in proteomics facilitate substrate discovery, we expect that shedding is not a rare exception, but rather the rule for many membrane proteins, and that many more interesting shedding functions await discovery.

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“…If this proteolytic interaction may have impact on neurodegenerative disorders has to be shown. Surprisingly, however, in a different study MT-2 was found to directly cleave neuronal APP695, but was effectively inhibited by the Kunitz protease inhibitor (KPI) domain present in other APP isoforms (APP751 and APP770) from the periphery (Beckmann et al, 2016). Of note, the additional domains in APP751 (KPI) and APP770 (KPI/OX2) do not lead to altered proteolytic processing by meprin β (Jefferson et al, 2011).…”

Section: Activationmentioning

confidence: 99%

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

Becker‐Pauly

Pietrzik

2017

Front. Mol. Neurosci.

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The membrane bound metalloprotease meprin β is important for collagen fibril assembly in connective tissue formation and for the detachment of the intestinal mucus layer for proper barrier function. Recent proteomic studies revealed dozens of putative new substrates of meprin β, including the amyloid precursor protein (APP). It was shown that APP is cleaved by meprin β in distinct ways, either at the β-secretase site resulting in increased levels of Aβ peptides, or at the N-terminus releasing 11 kDa, and 20 kDa peptide fragments. The latter event was discussed to be rather neuroprotective, whereas the ectodomain shedding of APP by meprin β reminiscent to BACE-1 is in line with the amyloid hypothesis of Alzheimer's disease, promoting neurodegeneration. The N-terminal 11 kDa and 20 kDa peptide fragments represent physiological cleavage products, since they are found in human brains under different diseased or non-diseased states, whereas these fragments are completely missing in brains of meprin β knock-out animals. Meprin β is not only a sheddase of adhesion molecules, such as APP, but was additionally demonstrated to cleave within the prodomain of ADAM10. Activated ADAM10, the α-secretase of APP, is then able to shed meprin β from the cell surface thereby abolishing the β-secretase activity. All together meprin β seems to be a novel player in APP processing events, even influencing other enzymes involved in APP cleavage.

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The intact Kunitz domain protects the amyloid precursor protein from being processed by matriptase-2

Cited by 10 publications

References 40 publications

Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain

Mapping the transcriptional diversity of genetically and anatomically defined cell populations in the mouse brain

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

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