BCL-XL dimerization by three-dimensional domain swapping.
Dimeric interactions among anti- and pro-apoptotic members of the BCL-2 protein family are dynamically regulated and intimately involved in survival and death functions. We report the structure of a BCL-X(L) homodimers a 3D-domain swapped dimer (3DDS). The X-ray crystal structure demonstrates the mutual exchange of carboxy-terminal regions including BH2 (Bcl-2 homology 2) between monomer subunits, with the hinge region occurring at the hairpin turn between the fifth and sixth alpha helices. Both BH3 peptide-binding hydrophobic grooves are unoccupied in the 3DDS dimer and available for BH3 peptide binding, as confirmed by sedimentation velocity analysis. BCL-X(L) 3DDS dimers have increased pore-forming activity compared to monomers, suggesting that 3DDS dimers may act as intermediates in membrane pore formation. Chemical crosslinking studies of Cys-substituted BCL-X(L) proteins demonstrate that 3DDS dimers form in synthetic lipid vesicles.
O'Neill
Jason W
JW
Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Manion
Michael K
MK
Maguire
Brendan
B
Hockenbery
David M
DM
D003432:Cross-Linking Reagents / Q000737:chemistry; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051020:bcl-X Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C494811:BCL2L1 protein, human; C474007:Bax protein (53-86); D003432:Cross-Linking Reagents; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D051020:bcl-X Protein