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PDBsum entry 6vec
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Protein fibril
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PDB id
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6vec
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Contents |
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(+ 5 more)
370 a.a.
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(+ 5 more)
241 a.a.
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References listed in PDB file
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Key reference
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Title
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Osteogenesis imperfecta mutations in plastin 3 lead to impaired calcium regulation of actin bundling.
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Authors
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C.L.Schwebach,
E.Kudryashova,
W.Zheng,
M.Orchard,
H.Smith,
L.A.Runyan,
E.H.Egelman,
D.S.Kudryashov.
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Ref.
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Bone Res, 2020,
8,
21.
[DOI no: ]
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PubMed id
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Abstract
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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 Ca2+ sensitivity: two of
the mutants lost the ability to be inhibited by Ca2+, while the other
two became hypersensitive to Ca2+. Each group of the mutants with
similar biochemical properties showed highly characteristic cellular behavior.
Wild-type PLS3 was distributed between lamellipodia and focal adhesions. In
striking contrast, the Ca2+-hyposensitive mutants were not found at
the leading edge but localized exclusively at focal adhesions/stress fibers,
which displayed reinforced morphology. Consistently, the
Ca2+-hypersensitive PLS3 mutants were restricted to lamellipodia,
while chelation of Ca2+ caused their redistribution to focal
adhesions. Finally, the bundling-deficient mutant failed to co-localize with any
F-actin structures in cells despite a preserved F-actin binding through a
non-mutation-bearing actin-binding domain. Our findings revealed that severe
osteoporosis can be caused by a mutational disruption of the
Ca2+-controlled PLS3's cycling between adhesion complexes and the
leading edge. Integration of the structural, biochemical, and cell biology
insights enabled us to propose a molecular mechanism of plastin activity
regulation by Ca2+.
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