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肿瘤抑制因子 RASSF1A 的 SARAH 结构域与其有丝分裂激酶 Aurora A 之间的新型相互作用。

New type of interaction between the SARAH domain of the tumour suppressor RASSF1A and its mitotic kinase Aurora A.

机构信息

Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary.

ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.

出版信息

Sci Rep. 2019 Apr 3;9(1):5550. doi: 10.1038/s41598-019-41972-x.

DOI:10.1038/s41598-019-41972-x
PMID:30944388
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6447619/
Abstract

The tumour suppressor protein RASSF1A is phosphorylated by Aurora A kinase, thereby impairing its tumour suppressor function. Consequently, inhibiting the interaction between Aurora A and RASSF1A may be used for anti-tumour therapy. We used recombinant variants of RASSF1A to map the sites of interaction with Aurora A. The phosphorylation kinetics of three truncated RASSF1A variants has been analysed. Compared to the RASSF1A form lacking the 120 residue long N-terminal part, the K value of the phosphorylation is increased from 10 to 45 μM upon additional deletion of the C-terminal SARAH domain. On the other hand, deletion of the flexible loop (Δ177-197) that precedes the phosphorylation site/s (T202/S203) results in a reduction of the k value from about 40 to 7 min. Direct physical interaction between the isolated SARAH domain and Aurora A was revealed by SPR. These data demonstrate that the SARAH domain of RASSF1A is involved in the binding to Aurora A kinase. Structural modelling confirms that a novel complex is feasible between the SARAH domain and the kinase domain of Aurora A. In addition, a regulatory role of the loop in the catalytic phosphorylation reaction has been demonstrated both experimentally and by structural modelling.

摘要

肿瘤抑制蛋白 RASSF1A 可被 Aurora A 激酶磷酸化，从而损害其肿瘤抑制功能。因此，抑制 Aurora A 和 RASSF1A 之间的相互作用可能用于抗肿瘤治疗。我们使用 RASSF1A 的重组变体来绘制与 Aurora A 相互作用的位点。分析了三种截断的 RASSF1A 变体的磷酸化动力学。与缺乏 120 个残基长的 N 端部分的 RASSF1A 形式相比，当额外缺失 C 端 SARAH 结构域时，磷酸化的 K 值从 10 增加到 45 μM。另一方面，删除在磷酸化位点（T202/S203）之前的柔性环（Δ177-197）会导致 k 值从约 40 减少到 7 分钟。通过 SPR 揭示了分离的 SARAH 结构域和 Aurora A 之间的直接物理相互作用。这些数据表明 RASSF1A 的 SARAH 结构域参与与 Aurora A 激酶的结合。结构建模证实了 SARAH 结构域和 Aurora A 的激酶结构域之间存在新的复合物是可行的。此外，通过实验和结构建模证明了该环在催化磷酸化反应中的调节作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/19ef16c166e7/41598_2019_41972_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/0bde7b3d290b/41598_2019_41972_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/ced48aeae228/41598_2019_41972_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/624d13136db6/41598_2019_41972_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/c7096f9f4f0e/41598_2019_41972_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/d524f629bb99/41598_2019_41972_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/19ef16c166e7/41598_2019_41972_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/0bde7b3d290b/41598_2019_41972_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/ced48aeae228/41598_2019_41972_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/624d13136db6/41598_2019_41972_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/c7096f9f4f0e/41598_2019_41972_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/d524f629bb99/41598_2019_41972_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3777/6447619/19ef16c166e7/41598_2019_41972_Fig6_HTML.jpg

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