Characterizing the consensus residue specificity and surface of BCL-2 binding to BH3 ligands using the Knob-Socket model

Authors

• Jennifer Yi, University of California, Berkeley
• Vivian Kellner, University of California, Davis
• Hyun Joo, University of the PacificFollow
• Nathaniel Chien, Stanford Engineering
• Shivarni Patel, University of the PacificFollow
• Zaina Chaban, University of the Pacific
• Jerry Tsai, University of the PacificFollow

Document Type

Article

Publication Title

PloS One

Department

Chemistry

ISSN

19326203

Volume

18

Issue

2

DOI

10.1371/journal.pone.0281463

First Page

1

Last Page

17

Publication Date

2-16-2023

Abstract

Cancer cells bypass cell death by changing the expression of the BCL-2 family of proteins, which are apoptotic pathway regulators. Upregulation of pro-survival BCL-2 proteins or downregulation of cell death effectors BAX and BAK interferes with the initiation of the intrinsic apoptotic pathway. In normal cells, apoptosis can occur through pro-apoptotic BH3-only proteins interacting and inhibiting pro-survival BCL-2 proteins. When cancer cells over-express pro-survival BCL-2 proteins, a potential remedy is the sequestration of these pro-survival proteins through a class of anti-cancer drugs called BH3 mimetics that bind in the hydrophobic groove of pro-survival BCL-2 proteins. To improve the design of these BH3 mimetics, the packing interface between BH3 domain ligands and pro-survival BCL-2 proteins was analyzed using the Knob-Socket model to identify the amino acid residues responsible for interaction affinity and specificity. A Knob-Socket analysis organizes all the residues in a binding interface into simple 4 residue units: 3-residue sockets defining surfaces on a protein that pack a 4^th residue knob from the other protein. In this way, the position and composition of the knobs packing into sockets across the BH3/BCL-2 interface can be classified. A Knob-Socket analysis of 19 BCL-2 protein and BH3 helix co-crystals reveal multiple conserved binding patterns across protein paralogs. Conserved knob residues such as a Gly, Leu, Ala and Glu most likely define binding specificity in the BH3/BCL-2 interface, whereas other residues such as Asp, Asn, and Val are important for forming surface sockets that bind these knobs. These findings can be used to inform the design of BH3 mimetics that are specific to pro-survival BCL-2 proteins for cancer therapeutics.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Yi, Jennifer; Kellner, Vivian; Joo, Hyun; Chien, Nathaniel; Patel, Shivarni; Chaban, Zaina; and Tsai, Jerry, "Characterizing the consensus residue specificity and surface of BCL-2 binding to BH3 ligands using the Knob-Socket model" (2023). Pacific Faculty Work. 132.
https://scholarlycommons.pacific.edu/all-faculty/132