Neutron reflectometry and NMR spectroscopy of full-length Bcl-2 protein reveal its membrane localization and conformation.

Mushtaq AU, Ådén J, Clifton LA, Wacklin-Knecht H, Campana M, Dingeldein APG, Persson C, Sparrman T, Gröbner G

Commun Biol 4 (1) 507 [2021-04-27; online 2021-04-27]

B-cell lymphoma 2 (Bcl-2) proteins are the main regulators of mitochondrial apoptosis. Anti-apoptotic Bcl-2 proteins possess a hydrophobic tail-anchor enabling them to translocate to their target membrane and to shift into an active conformation where they inhibit pro-apoptotic Bcl-2 proteins to ensure cell survival. To address the unknown molecular basis of their cell-protecting functionality, we used intact human Bcl-2 protein natively residing at the mitochondrial outer membrane and applied neutron reflectometry and NMR spectroscopy. Here we show that the active full-length protein is entirely buried into its target membrane except for the regulatory flexible loop domain (FLD), which stretches into the aqueous exterior. The membrane location of Bcl-2 and its conformational state seems to be important for its cell-protecting activity, often infamously upregulated in cancers. Most likely, this situation enables the Bcl-2 protein to sequester pro-apoptotic Bcl-2 proteins at the membrane level while sensing cytosolic regulative signals via its FLD region.

Swedish NMR Centre (SNC) [Collaborative]

PubMed 33907308

DOI 10.1038/s42003-021-02032-1

Crossref 10.1038/s42003-021-02032-1

pii: 10.1038/s42003-021-02032-1
pmc: PMC8079415