STRUCTURAL SPECIFICITY OF MCL-1, A BCL-2 FAMILY PROTEIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Bcl2蛋白家族通过家族成员间的蛋白质相互作用来调节细胞凋亡。我们使用结构和突变研究来了解这些相互作用的特异性，特别是Mcl-1与不同BH3多肽的相互作用。MCL-1/Bim BH3复合体与其他Bcl2蛋白/Bim复合体相比，表现出不同的结构差异，包括与Bim BH3结合后的不同变化。对Bim BH3序列的突变研究表明，许多突变体，包括保守残基的突变，都能与Mcl-1和其他Bcl-2蛋白保持结合。Mcl-1与一些突变的Bim BH3肽形成的复合体的结构表明，BH3肽和Mcl-1蛋白的灵活性允许这些突变的适应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The Bcl-2 family of proteins regulates apoptosis via protein-protein interactions among family members. We use structural and mutagenesis studies to understand the specificity of these interactions, specifically Mcl-1 with different BH3 peptides. Mcl-1/Bim BH3 complexes compared with other Bcl-2 protein/Bim complexes show structural differences, including different changes upon binding of the Bim BH3. Mutagenesis studies of the Bim BH3 sequence indicate many mutants, including mutations of conserved residues, can maintain binding to Mcl-1 and other Bcl-2 proteins. Structures of Mcl-1 in complex with some of these mutant Bim BH3 peptides reveal that flexibility of the BH3 peptide and the Mcl-1 protein allows for the accommodation of these mutations.