Biochemistry Research Group, Department of Biological Sciences, University of Calgary, Calgary, Alberta, T2N 1N4, Canada.
Prostate Cancer Centre, Southern Alberta Institute of Urology, Rockyview General Hospital, Calgary, Alberta, T2V 1P9, Canada.
Sci Rep. 2017 Feb 1;7:40662. doi: 10.1038/srep40662.
L-plastin is a calcium-regulated actin-bundling protein that is expressed in cells of hematopoietic origin and in most metastatic cancer cells. These cell types are mobile and require the constant remodeling of their actin cytoskeleton, where L-plastin bundles filamentous actin. The calcium-dependent regulation of the actin-bundling activity of L-plastin is not well understood. We have used NMR spectroscopy to determine the solution structure of the EF-hand calcium-sensor headpiece domain. Unexpectedly, this domain does not bind directly to the four CH-domains of L-plastin. A novel switch helix is present immediately after the calcium-binding region and it binds tightly to the EF-hand motifs in the presence of calcium. We demonstrate that this switch helix plays a major role during actin-bundling. Moreover a peptide that competitively inhibits the association between the EF-hand motifs and the switch helix was shown to deregulate the actin-bundling activity of L-plastin. Overall, these findings may help to develop new drugs that target the L-plastin headpiece and interfere in the metastatic activity of cancer cells.
L-plastin 是一种钙调节的肌动蛋白束状蛋白，它在造血细胞和大多数转移性癌细胞中表达。这些细胞类型是移动的，需要不断重塑其肌动蛋白细胞骨架，其中 L-plastin 束状丝状肌动蛋白。L-plastin 的肌动蛋白束状活性的钙依赖性调节尚不清楚。我们使用 NMR 光谱法确定了 EF 手钙离子传感器头部结构域的溶液结构。出乎意料的是，该结构域不能直接与 L-plastin 的四个 CH 结构域结合。在钙结合区之后立即存在一个新颖的开关螺旋，并且在存在钙的情况下，它与 EF 手基序紧密结合。我们证明该开关螺旋在肌动蛋白束状中起主要作用。此外，竞争性抑制 EF 手基序和开关螺旋之间的结合的肽被证明可以使 L-plastin 的肌动蛋白束状活性失活。总体而言，这些发现可能有助于开发靶向 L-plastin 头部结构域并干扰癌细胞转移活性的新药。
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