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Domain-specific insight into the recognition of BH3-death motifs by the pro-survival Bcl-2 protein
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-5636-2567
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0002-4480-1219
Umeå University, Faculty of Science and Technology, Department of Chemistry.
Umeå University, Faculty of Science and Technology, Department of Chemistry.ORCID iD: 0000-0001-7380-8797
2022 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 121, no 23, p. 4517-4525Article in journal (Refereed) Published
Abstract [en]

Programmed mammalian cell death (apoptosis) is an essential mechanism in life that tightly regulates embryogenesis and removal of dysfunctional cells. In its intrinsic (mitochondrial) pathway, opposing members of the Bcl-2 (B cell lymphoma 2) protein family meet at the mitochondrial outer membrane (MOM) to control its integrity. Any imbalance can cause disorders, with upregulation of the cell-guarding antiapoptotic Bcl-2 protein itself being common in many, often incurable, cancers. Normally, the Bcl-2 protein itself is embedded in the MOM where it sequesters cell-killing apoptotic proteins such as Bax (Bcl-2-associated X protein) that would otherwise perforate the MOM and subsequently cause cell death. However, the molecular basis of Bcl-2’s ability to recognize those apoptotic proteins via their common BH3 death motifs remains elusive due to the lack of structural insight. By employing nuclear magnetic resonance on fully functional human Bcl-2 protein in membrane-mimicking micelles, we identified glycine residues across all functional domains of the Bcl-2 protein and could monitor their residue-specific individual response upon the presence of a Bax-derived 36aa long BH3 domain. The observed chemical shift perturbations allowed us to determine the response and individual affinity of each glycine residue and provide an overall picture of the individual roles by which Bcl-2’s functional domains engage in recognizing and inhibiting apoptotic proteins via their prominent BH3 motifs. This way, we provide a unique residue- and domain-specific insight into the molecular functioning of Bcl-2 at the membrane level, an insight also opening up for interfering with this cell-protecting mechanism in cancer therapy.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 121, no 23, p. 4517-4525
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-201021DOI: 10.1016/j.bpj.2022.10.041ISI: 000908349700011Scopus ID: 2-s2.0-85142005196OAI: oai:DiVA.org:umu-201021DiVA, id: diva2:1710976
Funder
Swedish Research CouncilSwedish Cancer SocietyThe Kempe FoundationsKnut and Alice Wallenberg FoundationAvailable from: 2022-11-15 Created: 2022-11-15 Last updated: 2023-09-05Bibliographically approved

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Ul Mushtaq, AmeeqÅdén, JörgenGröbner, Gerhard

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