000136438 001__ 136438 000136438 005__ 20240321220052.0 000136438 0247_ $$2doi$$a10.1074/jbc.M111.328104 000136438 0247_ $$2pmid$$apmid:22194595 000136438 0247_ $$2pmc$$apmc:PMC3281599 000136438 0247_ $$2ISSN$$a0021-9258 000136438 0247_ $$2ISSN$$a1067-8816 000136438 0247_ $$2ISSN$$a1083-351X 000136438 037__ $$aDZNE-2020-02760 000136438 041__ $$aEnglish 000136438 082__ $$a540 000136438 1001_ $$0P:(DE-2719)2000007$$aFluhrer, Regina$$b0$$eFirst author 000136438 245__ $$aThe α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). 000136438 260__ $$aBethesda, Md.$$bSoc.60645$$c2012 000136438 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2011-12-22 000136438 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2012-02-10 000136438 3367_ $$2DRIVER$$aarticle 000136438 3367_ $$2DataCite$$aOutput Types/Journal article 000136438 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1586955128_28578 000136438 3367_ $$2BibTeX$$aARTICLE 000136438 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000136438 3367_ $$00$$2EndNote$$aJournal Article 000136438 520__ $$aRegulated intramembrane proteolysis is a widely accepted concept describing the processing of various transmembrane proteins via ectodomain shedding followed by an intramembrane cleavage. The resulting cleavage products can be involved in reverse signaling. Presenilins, which constitute the active center of the γ-secretase complex, signal peptide peptidase (SPP), and its homologues, the SPP-like (SPPL) proteases are members of the family of intramembrane-cleaving aspartyl proteases of the GXGD-type. We recently demonstrated that Bri2 (itm2b) is a substrate for regulated intramembrane proteolysis by SPPL2a and SPPL2b. Intramembrane cleavage of Bri2 is triggered by an initial shedding event catalyzed by A Disintegrin and Metalloprotease 10 (ADAM10). Additionally primary sequence determinants within the intracellular domain, the transmembrane domain and the luminal juxtamembrane domain are required for efficient cleavage of Bri2 by SPPL2b. Using mutagenesis and circular dichroism spectroscopy we now demonstrate that a high α-helical content of the Bri2 transmembrane domain (TMD) reduces cleavage efficiency of Bri2 by SPPL2b, while the presence of a GXXXG dimerization motif influences the intramembrane cleavage only to a minor extent. Surprisingly, only one of the four conserved intramembrane glycine residues significantly affects the secondary structure of the Bri2 TMD and thereby its intramembrane cleavage. Other glycine residues do not influence the α-helical content of the transmembrane domain nor its intramembrane processing. 000136438 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0 000136438 588__ $$aDataset connected to CrossRef, PubMed, 000136438 650_7 $$2NLM Chemicals$$aITM2B protein, human 000136438 650_7 $$2NLM Chemicals$$aMembrane Glycoproteins 000136438 650_7 $$2NLM Chemicals$$aMembrane Proteins 000136438 650_7 $$0EC 3.4.-$$2NLM Chemicals$$aAmyloid Precursor Protein Secretases 000136438 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aAspartic Acid Endopeptidases 000136438 650_7 $$0EC 3.4.23.-$$2NLM Chemicals$$aSPPL2b protein, human 000136438 650_7 $$0EC 3.4.24.-$$2NLM Chemicals$$aADAM Proteins 000136438 650_7 $$0EC 3.4.24.81$$2NLM Chemicals$$aADAM10 Protein 000136438 650_7 $$0EC 3.4.24.81$$2NLM Chemicals$$aADAM10 protein, human 000136438 650_2 $$2MeSH$$aADAM Proteins: genetics 000136438 650_2 $$2MeSH$$aADAM Proteins: metabolism 000136438 650_2 $$2MeSH$$aADAM10 Protein 000136438 650_2 $$2MeSH$$aAmino Acid Motifs 000136438 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: genetics 000136438 650_2 $$2MeSH$$aAmyloid Precursor Protein Secretases: metabolism 000136438 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: genetics 000136438 650_2 $$2MeSH$$aAspartic Acid Endopeptidases: metabolism 000136438 650_2 $$2MeSH$$aCircular Dichroism: methods 000136438 650_2 $$2MeSH$$aHEK293 Cells 000136438 650_2 $$2MeSH$$aHumans 000136438 650_2 $$2MeSH$$aMembrane Glycoproteins 000136438 650_2 $$2MeSH$$aMembrane Proteins: genetics 000136438 650_2 $$2MeSH$$aMembrane Proteins: metabolism 000136438 650_2 $$2MeSH$$aMutagenesis 000136438 650_2 $$2MeSH$$aProtein Structure, Tertiary 000136438 650_2 $$2MeSH$$aProteolysis 000136438 7001_ $$0P:(DE-HGF)0$$aMartin, Lucas$$b1 000136438 7001_ $$0P:(DE-HGF)0$$aKlier, Bärbel$$b2 000136438 7001_ $$0P:(DE-HGF)0$$aHaug-Kröper, Martina$$b3 000136438 7001_ $$0P:(DE-HGF)0$$aGrammer, Gudula$$b4 000136438 7001_ $$0P:(DE-HGF)0$$aNuscher, Brigitte$$b5 000136438 7001_ $$0P:(DE-2719)2202037$$aHaass, Christian$$b6$$eLast author 000136438 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.m111.328104$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2011-12-22$$n7$$p5156-5163$$tJournal of Biological Chemistry$$v287$$x0021-9258$$y2011 000136438 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.M111.328104$$gVol. 287, no. 7, p. 5156 - 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