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A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases.

ABSTRACT: One of the most promising and as yet underutilized means of regulating protein function is exploitation of allosteric sites. All caspases catalyze the same overall reaction, but they perform different biological roles and are differentially regulated. It is our hypothesis that many allosteric sites exist on various caspases and that understanding both the distinct and overlapping mechanisms by which each caspase can be allosterically controlled should ultimately enable caspase-specific inhibition. Here we describe the ongoing work and methods for compiling a comprehensive map of apoptotic caspase allostery. Central to this approach are the use of (i) the embedded record of naturally evolved allosteric sites that are sensitive to zinc-mediated inhibition, phosphorylation, and other posttranslational modifications, (ii) structural and mutagenic approaches, and (iii) novel binding sites identified by both rationally-designed and screening-derived small-molecule inhibitors.

SUBMITTER: Dagbay K

PROVIDER: S-EPMC4237280 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases.

Dagbay Kevin K Eron Scott J SJ Serrano Banyuhay P BP Velázquez-Delgado Elih M EM Zhao Yunlong Y Lin Di D Vaidya Sravanti S Hardy Jeanne A JA

Methods in enzymology 20140101

One of the most promising and as yet underutilized means of regulating protein function is exploitation of allosteric sites. All caspases catalyze the same overall reaction, but they perform different biological roles and are differentially regulated. It is our hypothesis that many allosteric sites exist on various caspases and that understanding both the distinct and overlapping mechanisms by which each caspase can be allosterically controlled should ultimately enable caspase-specific inhibitio ...[more]

PMID: 24974292

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Project description:Caspases are well known proteases in the context of inflammation and apoptosis. Recently, novel roles of pro-apoptotic caspases have been reported, including findings related to the development of hard tissues. To further investigate these emerging functions of pro-apoptotic caspases, the in vivo localisation of key pro-apoptotic caspases (-3,-6,-7,-8, and -9) was assessed, concentrating on the development of two neighbouring hard tissues, cells participating in odontogenesis (represented by the first mouse molar) and intramembranous osteogenesis (mandibular/alveolar bone). The expression of the different caspases within the developing tissues was correlated with the apoptotic status of the cells, to produce a picture of whether different caspases have potentially distinct, or overlapping non-apoptotic functions. The in vivo investigation was additionally supported by examination of caspases in an osteoblast-like cell line in vitro. Caspases-3,-7, and -9 were activated in apoptotic cells of the primary enamel knot of the first molar; however, caspase-7 and -8 activation was also associated with the non-apoptotic enamel epithelium at the same stage and later with differentiating/differentiated odontoblasts and ameloblasts. In the adjacent bone, active caspases-7 and -8 were present abundantly in the prenatal period, while the appearance of caspases-3,-6, and -9 was marginal. Perinatally, caspases-3 and -7 were evident in some osteoclasts and osteoblastic cells, and caspase-8 was abundant mostly in osteoclasts. In addition, postnatal activation of caspases-7 and -8 was retained in osteocytes. The results provide a comprehensive temporo-spatial pattern of pro-apoptotic caspase activation, and demonstrate both unique and overlapping activation in non-apoptotic cells during development of the molar tooth and mandibular/alveolar bone. The importance of caspases in osteogenic pathways is highlighted by caspase inhibition in osteoblast-like cells, which led to a significant decrease in osteocalcin expression, supporting a role in hard tissue cell differentiation.

Dataset Information

A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases.

Publications

A multipronged approach for compiling a global map of allosteric regulation in the apoptotic caspases.

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