Energetics and Dynamics Across the Bcl-2-Regulated Apoptotic Pathway Reveal Distinct Evolutionary Determinants of Specificity and Affinity
| Autor: | Stefan M. Ivanov, Peter J. Bond, Roland G. Huber, Jim Warwicker |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Apoptosis Computational biology Biology Molecular Dynamics Simulation Protein–protein interaction Evolution Molecular 03 medical and health sciences Mice Structural Biology Manchester Institute of Biotechnology Gene duplication Animals Humans Protein Interaction Domains and Motifs Molecular Biology Binding Sites Intrinsic apoptotic pathway Energetics ResearchInstitutes_Networks_Beacons/manchester_institute_of_biotechnology Cell biology 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 Hydrophobic and Hydrophilic Interactions Protein Binding Signal Transduction |
| Zdroj: | Ivanov, S M, Huber, R G, Warwicker, J & Bond, P J 2016, ' Energetics and Dynamics Across the Bcl-2-Regulated Apoptotic Pathway Reveal Distinct Evolutionary Determinants of Specificity and Affinity ', Structure (London, England : 1993), vol. 24, no. 11, pp. 2024-2033 . https://doi.org/10.1016/j.str.2016.09.006 |
| ISSN: | 1878-4186 |
| DOI: | 10.1016/j.str.2016.09.006 |
| Popis: | Critical regulatory pathways are replete with instances of intra- and interfamily protein-protein interactions due to the pervasiveness of gene duplication throughout evolution. Discerning the specificity determinants within these systems has proven a challenging task. Here, we present an energetic analysis of the specificity determinants within the Bcl-2 family of proteins (key regulators of the intrinsic apoptotic pathway) via a total of ∼20 μs of simulation of 60 distinct protein-protein complexes. We demonstrate where affinity and specificity of protein-protein interactions arise across the family, and corroborate our conclusions with extensive experimental evidence. We identify energy and specificity hotspots that may offer valuable guidance in the design of targeted therapeutics for manipulating the protein-protein interactions within the apoptosis-regulating pathway. Moreover, we propose a conceptual framework that allows us to quantify the relationship between sequence, structure, and binding energetics. This approach may represent a general methodology for investigating other paralogous protein-protein interaction sites. |
| Databáze: | OpenAIRE |
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