Ligand Binding and Membrane Insertion Compete with Oligomerization of the BclXL Apoptotic Repressor

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• 作者：Vikas Bhat¹ ; Caleb B. McDonald¹ ; David C. Mikles¹ ; Brian J. Deegan¹ ; Kenneth L. Seldeen¹ ; Margaret L. Bates² ; Amjad Farooq¹ ; ^{amjad@farooqlab.net}
• 关键词：ALS ; analytical light scattering ; Bad ; Bcl2-associated death (promoter) ; Bak ; Bcl2 (homologous) antagonist/killer ; Bax ; Bcl2-associated X (protein) ; Bcl2 ; B-cell lymphoma 2 ; BclW ; B-cell lymphoma W ; BclXL ; B-cell lymphoma extra large ; BclXL_FL ; full-lengt
• 刊名：Journal of Molecular Biology
• 出版年：2012
• 出版时间：10 February 2012
• 年：2012
• 卷：416
• 期：1
• 页码：57-77
• 全文大小：1954 K

文摘

B-cell lymphoma extra large (BclXL) apoptotic repressor plays a central role in determining the fate of cells to live or die during physiological processes such as embryonic development and tissue homeostasis. Herein, using a myriad of biophysical techniques, we provide evidence that ligand binding and membrane insertion compete with oligomerization of BclXL in solution. Of particular importance is the observation that such oligomerization is driven by the intermolecular binding of its C-terminal transmembrane (TM) domain to the canonical hydrophobic groove in a domain-swapped trans fashion, whereby the TM domain of one monomer occupies the canonical hydrophobic groove within the other monomer and vice versa. Binding of BH3 ligands to the canonical hydrophobic groove displaces the TM domain in a competitive manner, allowing BclXL to dissociate into monomers upon hetero-association. Remarkably, spontaneous insertion of BclXL into DMPC/DHPC (1,2-dimyristoyl-sn-glycero-3-phosphocholine/1,2-dihexanoyl-sn-glycero-3-phosphocholine) bicelles results in a dramatic conformational change such that it can no longer recognize the BH3 ligands in what has come to be known as the ¡°hit-and-run?mechanism. Collectively, our data suggest that oligomerization of a key apoptotic repressor serves as an allosteric switch that fine-tunes its ligand binding and membrane insertion pertinent to the regulation of apoptotic machinery.