Analysis of BCL-2 and BH3 Complex Binding Patterns Using the Knob-Socket Model
Poster Number
7A
Format
Poster Presentation
Faculty Mentor Name
Jerry Tsai
Faculty Mentor Department
Department of Chemistry
Abstract/Artist Statement
The B-cell lymphoma 2 (BCL-2) protein family consists of apoptosis regulators and are often misregulated in cancer cells to avoid cell death. Pro-apoptotic and anti-apoptotic proteins in the family are differentiated by their BCL-2 homology (BH) domains. BAX and BAK are pro-apoptotic effector proteins that mediate intrinsic cell apoptosis via pore formation in the mitochondrial outer membrane. When cellular stress in non-cancerous cells initiates intrinsic signals to promote death, BH3 binds to the same hydrophobic groove on anti-apoptotic BCL-2’s as BAX and BAK, freeing the apoptosis effectors. Anti-apoptotic BCL-2’s inhibit the pro-apoptotic BAX and BAK proteins, and create cancer cells that are able to bypass activation of the intrinsic apoptosis pathway via the upregulation of anti-apoptotic BCL-2’s or the downregulation of pro-apoptotic BH3’s. The Knob-Socket model of protein packing represents protein tertiary and quaternary interactions via knobs packing into surfaces defined by three residue sockets. Patterns of knob-socket interactions can be analyzed for conserved packing by the helices found in anti-apoptotic BCL-2’s and BH3’s. A Knob-Socket analysis of 33 BCL-2:BH3 complexes found that a glycine-glycine interaction between an anti-apoptotic BCL-2’s helix five (H5) and BH3 was highly conserved and important for orienting the ligand to the binding pocket. With the glycine on H5 and BH3 set as position zero for sequence alignment, other conserved residue positions were found such as arginine in position +1 and phenylalanine in position +8. The Knob-Socket maps and sequence alignment can be used to better understand anti-apoptotic BCL-2 binding to BH3’s and utilized for designing BH3 mimetics for cancer therapeutics.
Location
Information Commons, William Knox Holt Memorial Library and Learning Center
Start Date
29-4-2023 10:00 AM
End Date
29-4-2023 1:00 PM
Analysis of BCL-2 and BH3 Complex Binding Patterns Using the Knob-Socket Model
Information Commons, William Knox Holt Memorial Library and Learning Center
The B-cell lymphoma 2 (BCL-2) protein family consists of apoptosis regulators and are often misregulated in cancer cells to avoid cell death. Pro-apoptotic and anti-apoptotic proteins in the family are differentiated by their BCL-2 homology (BH) domains. BAX and BAK are pro-apoptotic effector proteins that mediate intrinsic cell apoptosis via pore formation in the mitochondrial outer membrane. When cellular stress in non-cancerous cells initiates intrinsic signals to promote death, BH3 binds to the same hydrophobic groove on anti-apoptotic BCL-2’s as BAX and BAK, freeing the apoptosis effectors. Anti-apoptotic BCL-2’s inhibit the pro-apoptotic BAX and BAK proteins, and create cancer cells that are able to bypass activation of the intrinsic apoptosis pathway via the upregulation of anti-apoptotic BCL-2’s or the downregulation of pro-apoptotic BH3’s. The Knob-Socket model of protein packing represents protein tertiary and quaternary interactions via knobs packing into surfaces defined by three residue sockets. Patterns of knob-socket interactions can be analyzed for conserved packing by the helices found in anti-apoptotic BCL-2’s and BH3’s. A Knob-Socket analysis of 33 BCL-2:BH3 complexes found that a glycine-glycine interaction between an anti-apoptotic BCL-2’s helix five (H5) and BH3 was highly conserved and important for orienting the ligand to the binding pocket. With the glycine on H5 and BH3 set as position zero for sequence alignment, other conserved residue positions were found such as arginine in position +1 and phenylalanine in position +8. The Knob-Socket maps and sequence alignment can be used to better understand anti-apoptotic BCL-2 binding to BH3’s and utilized for designing BH3 mimetics for cancer therapeutics.