In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2
Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not w...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | en_US |
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American Chemical Society (ACS)
2014
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| Online Access: | http://hdl.handle.net/1721.1/84624 https://orcid.org/0000-0003-4074-8980 |
| _version_ | 1810985148174303232 |
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| author | London, Nir Gulla, Stefano Keating, Amy E. Schueler-Furman, Ora |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology London, Nir Gulla, Stefano Keating, Amy E. Schueler-Furman, Ora |
| author_sort | London, Nir |
| collection | MIT |
| description | Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide–receptor complexes. For two prominent players, Bcl-xL and Mcl-1, we obtain good agreement with a large set of experimental SPOT array measurements and recapitulate the binding specificity of peptides derived by yeast display in a previous study. We extend our approach to a third member of this family, Bcl-2: we test our blind prediction of the binding of 180 BIM-derived peptides with a corresponding experimental SPOT array. Both prediction and experiment reveal a Bcl-2 binding specificity pattern that resembles that of Bcl-xL. Finally, we extend this application to accurately predict the specificity pattern of additional human BH3-only derived peptides. This study characterizes the distinct patterns of binding specificity of BH3-only derived peptides for the Bcl-2 like proteins Bcl-xL, Mcl-1, and Bcl-2 and provides insight into the structural basis of determinants of specificity. |
| first_indexed | 2024-09-23T11:13:43Z |
| format | Article |
| id | mit-1721.1/84624 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:13:43Z |
| publishDate | 2014 |
| publisher | American Chemical Society (ACS) |
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| spelling | mit-1721.1/846242022-10-01T02:12:03Z In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 London, Nir Gulla, Stefano Keating, Amy E. Schueler-Furman, Ora Massachusetts Institute of Technology. Department of Biology Gulla, Stefano Keating, Amy E. Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide–receptor complexes. For two prominent players, Bcl-xL and Mcl-1, we obtain good agreement with a large set of experimental SPOT array measurements and recapitulate the binding specificity of peptides derived by yeast display in a previous study. We extend our approach to a third member of this family, Bcl-2: we test our blind prediction of the binding of 180 BIM-derived peptides with a corresponding experimental SPOT array. Both prediction and experiment reveal a Bcl-2 binding specificity pattern that resembles that of Bcl-xL. Finally, we extend this application to accurately predict the specificity pattern of additional human BH3-only derived peptides. This study characterizes the distinct patterns of binding specificity of BH3-only derived peptides for the Bcl-2 like proteins Bcl-xL, Mcl-1, and Bcl-2 and provides insight into the structural basis of determinants of specificity. National Institutes of Health (U.S.) (R01GM84181) 2014-01-31T17:35:47Z 2014-01-31T17:35:47Z 2012-06 2012-06 Article http://purl.org/eprint/type/JournalArticle 0006-2960 1520-4995 http://hdl.handle.net/1721.1/84624 London, Nir, Stefano Gulla, Amy E. Keating, and Ora Schueler-Furman. “In Silico and in Vitro Elucidation of BH3 Binding Specificity toward Bcl-2.” Biochemistry 51, no. 29 (July 24, 2012): 5841-5850. https://orcid.org/0000-0003-4074-8980 en_US http://dx.doi.org/10.1021/bi3003567 Biochemistry Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf American Chemical Society (ACS) PMC |
| spellingShingle | London, Nir Gulla, Stefano Keating, Amy E. Schueler-Furman, Ora In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title | In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title_full | In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title_fullStr | In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title_full_unstemmed | In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title_short | In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2 |
| title_sort | in silico and in vitro elucidation of bh3 binding specificity towards bcl 2 |
| url | http://hdl.handle.net/1721.1/84624 https://orcid.org/0000-0003-4074-8980 |
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