Osteogenesis imperfecta mutations in plastin 3 lead to impaired calcium regulation of actin bundling.

Christopher L Schwebach, Elena Kudryashova, Weili Zheng, Matthew Orchard, Harper Smith, Lucas A Runyan, Edward H Egelman, Dmitri S Kudryashov


Mutations in actin-bundling protein plastin 3 (PLS3) emerged as a cause of congenital osteoporosis, but neither the role of PLS3 in bone development nor the mechanisms underlying PLS3-dependent osteoporosis are understood. Of the over 20 identified osteoporosis-linked PLS3 mutations, we investigated all five that are expected to produce full-length protein. One of the mutations distorted an actin-binding loop in the second actin-binding domain of PLS3 and abolished F-actin bundling as revealed by cryo-EM reconstruction and protein interaction assays. Surprisingly, the remaining four mutants fully retained F-actin bundling ability. However, they displayed defects in Ca