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Osteogenesis Scholarly Peer-review Journal | Open Access Journals
Journal of Physiotherapy & Physical Rehabilitation

Journal of Physiotherapy & Physical Rehabilitation

ISSN: 2573-0312

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Osteogenesis Scholarly Peer-review Journal

Mutations in actin-grouping protein plastin 3 (PLS3) have emerged as a cause of congenital osteoporosis, but neither the role of PLS3 in bone development nor the mechanisms underlying PLS3-dependent osteoporosis are not understood. Of the 20 osteoporosis-related PLS3 mutations identified, we studied the five that are expected to produce full-length proteins. One of the mutations deformed an actin binding loop in the second actin binding domain of PLS3 and abolished the F-actin grouping as revealed by cryo-EM reconstruction and interaction tests proteins. Surprisingly, the remaining four mutants fully retained the pooling ability of F-actin. However, they showed defects in sensitivity to Ca2 +: two of the mutants lost the ability to be inhibited by Ca2 +, while the other two became hypersensitive to Ca2 +. Each group of mutants with similar biochemical properties showed highly characteristic cellular behavior. The wild type PLS3 was distributed between the lamellipods and the focal adhesions. In stark contrast, the mutants hyposensitive to Ca2 + were not found at the leading edge but located exclusively at the level of focal adhesions / stress fibers, which exhibited a reinforced morphology. Consistently, the PLS3 mutants hypersensitive to Ca2 + were limited to the lamellipods, while the chelation of Ca2 + caused their redistribution to focal adhesions. Finally, the mutant deficient in bundling failed to co-localize with F actin structures in cells despite an actin F binding preserved through an actin binding domain not carrying a mutation. Our results revealed that severe osteoporosis can be caused by a mutational disruption of the PLS3 cycle controlled by Ca2 + between the adhesion complexes and the leading edge. The integration of structural, biochemical and cellular biology information allowed us to propose a molecular mechanism for regulating the activity of plastin by Ca2 +.

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Citations: 378

Journal of Physiotherapy & Physical Rehabilitation received 378 citations as per Google Scholar report

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