Long-Range Communication Network in the Type 1B Bone Morphogenetic Protein Receptor

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• 作者：Wilfredo Evangelista ; Lee-Chuan C. Yeh ; Aleksandra Gmyrek ; J. Ching Lee ; John C. Lee
• 刊名：Biochemistry
• 出版年：2015
• 出版时间：December 8, 2015
• 年：2015
• 卷：54
• 期：48
• 页码：7079-7088
• 全文大小：559K
• ISSN：1520-4995

文摘

Protein鈥損rotein interactions are recognized as a fundamental phenomenon that is intimately associated with biological functions and thus are ideal targets for developing modulators for regulating biological functions. A challenge is to identify a site that is situated away from but functionally connected to the protein鈥損rotein interface. We employed bone morphogenetic proteins (BMPs) and their receptors as a model system to develop a strategy for identifying such a network of communication. Accordingly, using computational analyses with the COREX/BEST algorithm, we uncovered an overall pattern connecting various regions of BMPR-1B ectodomain, including the four conserved residues in the protein鈥損rotein interface. In preparation for testing the long-range effects of mutations of distal residues for future studies, we examined the extent of measurable perturbation of the four conserved residues by determination of the conformation and relative affinities of these BMPR-1B mutants for ligands BMP-2, -6, and -7 and GDF-5. Results suggest no significant structural changes in the receptor but do suggest that the four residues play different roles in defining ligand affinity and both intra- and intermolecular interactions play a role in defining ligand affinity. Thus, these results established two primary but necessary goals: (1) the baseline knowledge of perturbation of conserved interfacial residues for future reference and (2) the ability of the computational approach to identify the distal residues connecting to the interfacial residues. The data presented here provide the foundation for future experiments to identify the effects of distal residues that affect the specificity and affinity of BMP recognition. Protein鈥損rotein interactions are integral reactions in essentially all biological activities such as gene regulation and age-related development. Often, diseases are consequences of the alteration of these intermacromolecular interactions, which are thus recognized as a legitimate target for developing modulators for regulating biological functions. One approach is to design ligands that bind to the protein鈥損rotein interface. Another is to identify an allosteric site, an advantage of which is bypassing the potential challenge in competing for high-affinity interfacial interactions or a specific interface in a superassembly of multiple macromolecules. However, a challenge of this approach is identifying a site that is situated away from but functionally connected to the protein鈥損rotein interface.