The α-Helical Content of the Transmembrane Domain of the British Dementia Protein-2 (Bri2) Determines Its Processing by Signal Peptide Peptidase-like 2b (SPPL2b)

Fluhrer, Regina; Martin, Lucas; Klier, Bärbel; Haug-Kröper, Martina; Grammer, Gudula; Nuscher, Brigitte; Haass, Christian

doi:10.1074/jbc.m111.328104

Cited by 36 publications

(43 citation statements)

References 40 publications

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“…This would provide a simple mechanism for the preferred cleavage of APP in three amino acid increments, as well as provide an explanation for why γ-secretase mostly sticks to each major pathway, producing Aβ40 or Aβ42 after initiating cleavage of APP at either the L49 or T48 ε sites, respectively. Additionally, given that substrate movement in the form of helical unwinding is thought to be a required step in the poorly defined intramembrane protease cleavage mechanism (Akiyama et al, 2015; Dickey et al, 2013; Fluhrer et al, 2012; Moin and Urban, 2012; Urban and Freeman, 2003; Ye et al, 2000), the three S’ pockets could potentially provide a means for γ-secretase to stabilize its helical substrate in a more cleavable conformation, thereby lowering the activation energy required for catalysis.…”

Section: Resultsmentioning

confidence: 99%

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

Bolduc

Montagna

Seghers

et al. 2016

eLife

144

204

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γ-secretase is responsible for the proteolysis of amyloid precursor protein (APP) into short, aggregation-prone amyloid-beta (Aβ) peptides, which are centrally implicated in the pathogenesis of Alzheimer’s disease (AD). Despite considerable interest in developing γ-secretase targeting therapeutics for the treatment of AD, the precise mechanism by which γ-secretase produces Aβ has remained elusive. Herein, we demonstrate that γ-secretase catalysis is driven by the stabilization of an enzyme-substrate scission complex via three distinct amino-acid-binding pockets in the enzyme’s active site, providing the mechanism by which γ-secretase preferentially cleaves APP in three amino acid increments. Substrate occupancy of these three pockets occurs after initial substrate binding but precedes catalysis, suggesting a conformational change in substrate may be required for cleavage. We uncover and exploit substrate cleavage preferences dictated by these three pockets to investigate the mechanism by which familial Alzheimer’s disease mutations within APP increase the production of pathogenic Aβ species.DOI: http://dx.doi.org/10.7554/eLife.17578.001

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Section: Resultsmentioning

confidence: 99%

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

Bolduc

Montagna

Seghers

et al. 2016

eLife

144

204

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“…Although until now GxGD aspartyl intramembrane proteases were believed to depend on helix-destabilizing residues in the substrates' TMD and so far unidentified determinants within the juxtamembrane domain for substrate recognition and cleavage, rhomboid intramembrane proteases seem to require a distinct consensus cleavage site in or close to the luminal juxtamembrane domain of the substrate (13,(37)(38)(39). Our findings point toward a putative SPPL3 cleavage consensus motif localized in a transmembrane domain part embedded adjacent to the luminal plasma membrane boundary, which at least partially might influence SPPL3 substrate selectivity.…”

Section: Discussionmentioning

confidence: 99%

Secretome Analysis Identifies Novel Signal Peptide Peptidase-Like 3 (SPPL3) Substrates and Reveals a Role of SPPL3 in Multiple Golgi Glycosylation Pathways*

Kuhn

Voß

Haug-Kröper

et al. 2015

Molecular & Cellular Proteomics

Self Cite

111

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Signal peptide peptidase-like 3 (SPPL3) is a Golgi-resident intramembrane-cleaving protease that is highly conserved among multicellular eukaryotes pointing to pivotal physiological functions in the Golgi network which are only beginning to emerge. Recently, SPPL3 was shown to control protein N-glycosylation, when the key branching enzyme N-acetylglucosaminyltransferase V (GnT-V) and other medial/trans Golgi glycosyltransferases were identified as first physiological SPPL3 substrates. SPPL3-mediated endoproteolysis releases the catalytic ectodomains of these enzymes from their type II membrane anchors. Protein glycosylation is a multistep process involving numerous type II membrane-bound enzymes, but it remains unclear whether only few of them are SPPL3 substrates or whether SPPL3 cleaves many of them and thereby controls protein glycosylation at multiple levels. Therefore, to systematically identify SPPL3 substrates we used Sppl3-deficient and SPPL3-overexpression cell culture models and analyzed them for changes in secreted membrane protein ectodomains using the proteomics "secretome protein enrichment with click sugars (SPECS)" method. SPECS analysis identified numerous additional new SPPL3 candidate glycoprotein substrates, several of which were biochemically validated as SPPL3 substrates. All novel SPPL3 substrates adopt a type II topology. The majority localizes to the Golgi network and is implicated in Golgi functions. Importantly, most of the novel SPPL3 substrates catalyze the modification of Nlinked glycans. Others contribute to O-glycan and in particular glycosaminoglycan biosynthesis, suggesting that SPPL3 function is not restricted to N-glycosylation, but also functions in other forms of protein glycosylation. Hence, SPPL3 emerges as a crucial player of Golgi function and the newly identified SPPL3 substrates will be instrumental to investigate the molecular mechanisms underlying the physiological function of SPPL3 in the Golgi network and in vivo. Data are available via ProteomeXchange with identifier PXD001672. Molecular

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“…Thus, it is unlikely that the GxxxG motifs could contribute to heterodimerization between APP and APLP2. The British dementia protein-2 (BRI2 or integral membrane protein 2B/ITM2B), a protein associated with familial Danish and British dementia, possesses a GxxxG motif that could form dimerization complexes through helix-helix interactions with APP [85, 86] . In addition, the GxxxG motifs in APP transmembrane domain could serve as signals for guided intracellular transport from endoplasmic reticulum compartment to cell surface [86–88] .…”

Section: The Role Of App Subdomains In Dimerization Processmentioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

112

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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The α-Helical Content of the Transmembrane Domain of the British Dementia Protein-2 (Bri2) Determines Its Processing by Signal Peptide Peptidase-like 2b (SPPL2b)

Cited by 36 publications

References 40 publications

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase

Secretome Analysis Identifies Novel Signal Peptide Peptidase-Like 3 (SPPL3) Substrates and Reveals a Role of SPPL3 in Multiple Golgi Glycosylation Pathways*

APP Receptor? To Be or Not To Be

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