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

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

Author information

1
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary.
2
ELTE NAP Neuroimmunology Research Group, Department of Biochemistry, Institute of Biology, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
3
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary. hajdu.istvan@ttk.mta.hu.
4
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2., H-1117, Budapest, Hungary. vas.maria@ttk.mta.hu.

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 Km 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 kcat value from about 40 to 7 min-1. 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.

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