Talk Abstracts

Talk on Thursday 09:35-09:55am submitted by Dmitri Kudryashov

Just enough: the right level of plastin’s sensitivity to calcium for strong bones.

Dmitri Kudryashov (The Ohio State University), Elena Kudryashova, Christropher Schwebach (The Ohio State University), Weili Zheng, Edward Egelman (University of Virginia), Matthew Orchard (The Ohio State University), Harper Smitrh (The Ohio State University), Lucas Runyan (The Ohio State University)

Abstract:
Research in Kudryashov’s lab is focused on two broadly defined areas: host-pathogen interactions and the actin cytoskeleton organization and function in health and disease.
Osteogenesis imperfecta (OI) is the congenital form of osteoporosis that develops largely due to defects in collagen biogenesis. However, mutations in actin-bundling protein plastin-3 (PLS3) have recently emerged as an alternative cause of this “fragile bone disease”. Plastins belong to a large family of tandem calponin homology (tCH) actin-binding proteins. Plastins contain four CH domains, organized in two actin-binding domains (ABDs), and the N-terminal calcium-binding regulatory domain. Binding of Ca²⁺ to plastins reduces their actin-bundling ability.
Of nearly two dozen recognized osteoporosis-linked mutations in the PLS3 gene, only five are predicted to form full-length protein products. Of these, only the PLS3 mutant with L478P substitution in the second actin binding domain (ABD2) lost the ability to bundle actin due to major disorganization of an actin contacting loop. All the remaining mutants bundled actin well but showed either increased or reduced sensitivity to Ca²⁺, despite that the Ca²⁺-binding domain is not directly affected by the mutations. While wt PLS3 that is distributed between lamellipodia and focal adhesions, the OI-linked calcium-hypersensitive mutants were restricted to lamellipodia, while calcium-hyposensitive mutants were enriched only in focal adhesions/stress fibers. We propose a model of PLS3 regulation by Ca²⁺ and demonstrate that the finely-tuned Ca²⁺ regulation of PLS3 controls its cycling between the leading edge and adhesion complexes, contributing to bone formation via yet unknown mechanisms.

Keywords: congenital osteoporosis, actin cytoskeleton, regulation by calcium