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000154229 1001_ $$0P:(DE-HGF)0$$aSpitz, Charlotte$$b0
000154229 245__ $$aNon-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix.
000154229 260__ $$aSt. Louis$$bElsevier$$c2020
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000154229 520__ $$aEctodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate's TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future.
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000154229 650_7 $$2Other$$aBiophysics
000154229 650_7 $$2Other$$aStructural Biology
000154229 7001_ $$0P:(DE-2719)2812339$$aSchlosser, Christine$$b1$$udzne
000154229 7001_ $$0P:(DE-HGF)0$$aGuschtschin-Schmidt, Nadja$$b2
000154229 7001_ $$0P:(DE-HGF)0$$aStelzer, Walter$$b3
000154229 7001_ $$0P:(DE-HGF)0$$aMenig, Simon$$b4
000154229 7001_ $$0P:(DE-HGF)0$$aGötz, Alexander$$b5
000154229 7001_ $$0P:(DE-HGF)0$$aHaug-Kröper, Martina$$b6
000154229 7001_ $$0P:(DE-HGF)0$$aScharnagl, Christina$$b7
000154229 7001_ $$0P:(DE-2719)9001125$$aLangosch, Dieter$$b8$$udzne
000154229 7001_ $$0P:(DE-HGF)0$$aMuhle-Goll, Claudia$$b9
000154229 7001_ $$0P:(DE-2719)2000007$$aFluhrer, Regina$$b10$$eLast author
000154229 773__ $$0PERI:(DE-600)2927064-9$$a10.1016/j.isci.2020.101775$$gVol. 23, no. 12, p. 101775 -$$n12$$p101775$$tiScience$$v23$$x2589-0042$$y2020
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