The N-terminal domain of Bcl-xL reversibly binds membranes in a pH-dependent manner. Biochemistry 2006 Dec 05;45(48):14533-42
Date
11/30/2006Pubmed ID
17128992Pubmed Central ID
PMC1764622DOI
10.1021/bi0616652Scopus ID
2-s2.0-33845273500 (requires institutional sign-in at Scopus site) 34 CitationsAbstract
Bcl-xL regulates apoptosis by maintaining the integrity of the mitochondrial outer membrane by adopting both soluble and membrane-associated forms. The membrane-associated conformation does not require a conserved, C-terminal transmembrane domain and appears to be inserted into the bilayer of synthetic membranes as assessed by membrane permeabilization and critical surface pressure measurements. Membrane association is reversible and is regulated by the cooperative binding of approximately two protons to the protein. Two acidic residues, Glu153 and Asp156, that lie in a conserved hairpin of Bcl-xLDeltaTM appear to be important in this process on the basis of a 16% increase in the level of membrane association of the double mutant E153Q/D156N. Contrary to that for the wild type, membrane permeabilization for the mutant is not correlated with membrane association. Monolayer surface pressure measurements suggest that this effect is primarily due to less membrane penetration. These results suggest that E153 and D156 are important for the Bcl-xLDeltaTM conformational change and that membrane binding can be distinct from membrane permeabilization. Taken together, these studies support a model in which Bcl-xL activity is controlled by reversible insertion of its N-terminal domain into the mitochondrial outer membrane. Future studies with Bcl-xL mutants such as E153Q/D156N should allow determination of the relative contributions of membrane binding, insertion, and permeabilization to the regulation of apoptosis.
Author List
Thuduppathy GR, Terrones O, Craig JW, Basañez G, Hill RBMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceCell Membrane
Cell Membrane Permeability
Conserved Sequence
Hydrogen-Ion Concentration
Hydrophobic and Hydrophilic Interactions
Models, Molecular
Molecular Sequence Data
Mutation
Pressure
Protein Binding
Protein Structure, Tertiary
Solutions
bcl-X Protein
