A Novel Mechanism of Human Plastin Regulation
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Date
2018-03
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Abstract
The actin cytoskeleton is a vast network intricately regulated by numerous actin-binding proteins. Plastins are one family of these actin-binding proteins that non-covalently crosslink actin into bundles and contribute to a variety of cellular processes including cell migration and invasion. Plastin2 (PLS2) is expressed in hematopoietic cells and contributes to the activation, migration, and invasion of these cells and is also ectopically expressed in ~70% of epithelial cancers contributing to their metastatic capabilities. Actin bundling is achieved upon binding of two actin-binding domains (ABD1 and ABD2) to actin filaments. Our recently published data show that the ABDs are not functionally equal. ABD1 is the primary, low affinity domain whereas ABD2 is the secondary regulated domain. We have used a variety of biochemical, fluorescent, and microscopic techniques to determine the nature of the ABD1 – ABD2 interaction. We found that ABD2 binds actin with a low nanomolar affinity and can nucleate new filaments, properties not observed with full-length PLS2. Intriguingly, we observed that ABD1 is able to inhibit actin nucleation by ABD2 when introduced in trans and that the domains bind each other with a high affinity. In addition, we characterized ABD1 mutations that disrupt the ABD1/2 interaction and found that ABD1 binding actin releases the inhibition of ABD2. These data support a novel mode of plastin regulation where ABD1 allosterically inhibits ABD2. Upon ABD1-actin binding and upon phosphorylation, ABD2 inhibition is released allowing bundling.
Description
Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Actin, Plastin, Fimbrin, Biochemistry