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Analysis and design of protein interactions that regulate cell death

调节细胞死亡的蛋白质相互作用的分析和设计

基本信息

批准号：
10018034
负责人：
AMY E KEATING
金额：
$ 31.22万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018034
关键词：
Address Affect Affinity Apoptosis Apoptotic Area Autophagocytosis BAX gene BCL-2 Protein BCL2 gene Binding Binding Proteins Biological Biological Assay Biological Process Biology Cell Death Cell Death Signaling Process Cell Survival Cell surface Cells Cessation of life Code Complex Computer Models Computing Methodologies Diagnosis Disease Evolution Family Foundations Funding Grant Health Heart Diseases Human Immune response Ischemia Lead Libraries Life MCL1 gene Malignant Neoplasms Maps Mediating Membrane Methodology Methods Mitochondria Modeling Molecular Molecular Conformation Motivation Outcome Outer Mitochondrial Membrane Pathway interactions Peptides Pharmaceutical Preparations Play Process Protein Engineering Protein Family Proteins Proteome Reagent Regulation Research Role Route Signal Transduction Structural Models Structure Structure-Activity Relationship Technology Testing Therapeutic Therapeutic Intervention Time Variant Work alpha helix bak protein base biophysical analysis cancer therapy design experimental study human disease improved inhibitor/antagonist insight member mitochondrial membrane neoplastic cell nervous system disorder novel novel strategies pro-apoptotic protein protein function protein protein interaction prototype screening small molecule success therapeutic development therapy development tool working group

项目摘要

Protein-protein interactions control myriad biological processes important for human health. Tools for discovering, predicting and designing such interactions can provide insights into biological mechanisms and highlight possible routes to therapeutic intervention. This project will integrate computational and experimental approaches to advance our understanding of the relationships between sequence and function for protein interactions among Bcl-2 family proteins. The Bcl-2 family regulates apoptosis and autophagy by forming specific complexes, some of which inhibit and some of which promote cell death. Competition between pro- and anti-apoptotic Bcl-2 family proteins for binding to short alpha helices encoded by a Bcl-2 homology 3 (BH3) motif controls key cell survival decisions. It is now well established that peptides and small molecules can mimic or inhibit BH3 interactions. Such molecules provide a way to control signaling outcomes using exogenous reagents, as demonstrated by the first drug approved for treating cancer by targeting Bcl-2. Despite exciting progress, open questions about Bcl-2 protein interactions with BH3 motifs provide additional opportunities for discovery. In particular: Do as-yet undiscovered BH3 motif-containing proteins in the human proteome influence signaling through Bcl-2 family proteins? Why do some proteins that contain BH3 motifs trigger mitochondrial pore formation by pro-apoptotic BAK and BAX whereas others do not? What are the mechanisms of BH3 binding-induced conformational changes that lead to mitochondrial membrane pore formation and cell death? What opportunities exist for promoting or blocking such processes using designed peptides or proteins? Answers to these questions will impact analysis of Bcl-2 pathways important for multiple human diseases, provide new reagents, and guide development of therapies for cancer and other diseases. Building on the substantial successes that we realized in the previous funding period, we will drive progress in these areas by applying new methodology that integrates interaction screening with structural modeling and prediction. We will apply novel computational methods for predicting new Bcl-2 binding partners, test predictions of our models, and highlight candidate new interaction partners of biological significance. We will propose molecular mechanisms of BAK and BAX activation and test them using libraries of BH3 motif variants. We will apply new computational design methods to make peptides and mini-proteins that activate or inhibit BAK and BAX-mediated cell death. Collectively, our contributions will provide a map of the sequence-function landscape of BH3 motifs, which are critical factors controlling cell survival. The methods and tools developed in this work will also be useful for discovering and inhibiting other protein-protein interactions. !

蛋白质-蛋白质相互作用控制着对人类健康至关重要的无数生物过程。工具发现、预测和设计这种相互作用可以提供对生物机制的深入了解并强调治疗干预的可能途径。该项目将整合计算和实验方法，以促进我们的理解之间的关系序列和在Bcl-2家族蛋白之间的蛋白质相互作用中起作用。Bcl-2家族调节细胞凋亡，自噬通过形成特定的复合物，其中一些抑制和其中一些促进细胞死亡。促凋亡和抗凋亡Bcl-2家族蛋白与短α螺旋结合的竞争由Bcl-2同源性3（BH 3）基序编码的基因控制关键的细胞存活决定。现在得到确认的肽和小分子可以模拟或抑制BH 3的相互作用。这样的分子提供了一种使用外源性试剂控制信号传导结果，如第一种批准用于通过靶向Bcl-2治疗癌症。尽管取得了令人兴奋的进展，但关于Bcl-2蛋白的开放问题与BH 3基序的相互作用提供了额外的发现机会。特别是：目前为止人类蛋白质组中未发现的含BH 3基序的蛋白质通过Bcl-2影响信号传导家族蛋白质？为什么一些含有BH 3基序的蛋白质会通过以下方式触发线粒体孔的形成？促凋亡巴克和BAX，而其他则否？BH 3结合诱导细胞凋亡的机制是什么导致线粒体膜孔形成和细胞死亡的构象变化？什么存在使用设计的肽或蛋白质来促进或阻断这种过程的机会吗？这些问题的答案将影响Bcl-2通路的分析，这对多个人类疾病，提供新的试剂，并指导癌症和其他疾病的治疗方法的发展。在上一个资助期取得的巨大成功的基础上，我们将推动在这些领域取得进展，采用新的方法，将相互作用筛选与结构建模和预测。我们将应用新的计算方法来预测新的Bcl-2结合合作伙伴，测试我们的模型的预测，并突出候选的新的相互作用伙伴的生物意义我们将提出巴克和BAX激活的分子机制，并使用 BH 3基序变体的文库。我们将应用新的计算设计方法来制造肽，激活或抑制巴克和BAX介导的细胞死亡的小蛋白。我们的共同贡献将提供了BH 3基序的序列-功能图谱，这是控制基因表达的关键因素。细胞存活在这项工作中开发的方法和工具也将有助于发现和抑制其他蛋白质-蛋白质相互作用。 !

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Potent and specific peptide inhibitors of human pro-survival protein Bcl-xL.

DOI：
10.1016/j.jmb.2014.09.030
发表时间：
2015-03-27
期刊：
JOURNAL OF MOLECULAR BIOLOGY
影响因子：
5.6
作者：
Dutta, Sanjib;Ryan, Jeremy;Chen, T. Scott;Kougentakis, Christos;Letai, Anthony;Keating, Amy E.
通讯作者：
Keating, Amy E.

Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection.