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BCL-XL dimerization by three-dimensional domain swapping
Jason W O'Neill1, Michael K Manion, Brendan Maguire
1Divisions of Clinical Research and Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Journal of Molecular Biology
|December 22, 2005
Summary
The BCL-X(L) protein forms 3D-domain swapped dimers (3DDS) with available binding sites. These BCL-X(L) 3DDS dimers exhibit enhanced pore-forming activity, potentially acting as intermediates in membrane pore formation.
Area of Science:
- Molecular Biology
- Structural Biology
- Biochemistry
Background:
- Dimeric interactions of BCL-2 family proteins regulate cell survival and apoptosis.
- BCL-X(L) is a key regulator in cell death pathways.
Purpose of the Study:
- To determine the structure of BCL-X(L) homodimers.
- To investigate the functional implications of BCL-X(L) dimerization.
Main Methods:
- X-ray crystallography to determine 3D structure.
- Sedimentation velocity analysis to assess binding.
- Chemical crosslinking studies in lipid vesicles.
Main Results:
- The crystal structure revealed a 3D-domain swapped dimer (3DDS) of BCL-X(L) with exchanged carboxy-terminal regions.
- Both BH3 peptide-binding grooves in the 3DDS dimer remain unoccupied and available for binding.
- BCL-X(L) 3DDS dimers show increased pore-forming activity compared to monomers.
- 3DDS dimers were observed to form within synthetic lipid vesicles.
Conclusions:
- The 3D-domain swapped dimer is a significant structural form of BCL-X(L).
- BCL-X(L) 3DDS dimers may serve as intermediates in the process of membrane pore formation.
- Dimerization influences the function of BCL-X(L) in cellular processes.
