Isc10, an inhibitor of the Smk1 MAPK, prevents activation loop autophosphorylation and substrate phosphorylation through separate mechanisms.
Isc10, an inhibitor of the Smk1 MAPK, prevents activation loop autophosphorylation and substrate phosphorylation through separate mechanisms.
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DOI：
10.1016/j.jbc.2022.102450
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发表时间：
2022-10
影响因子：
4.8
通讯作者：
Winter, Edward
中科院分区：
文献类型：
--
作者：
Rimal, Abhimannyu;Swayne, Thomas M.;Kamdar, Zeal P.;Tewey, Madison A.;Winter, Edward
许多真核蛋白激酶是通过活化环残基的分子内自磷酸化而激活的。Smk1是酵母中减数分裂特异性丝裂原活化蛋白激酶（MAPK），其自磷酸化其激活环酪氨酸，从而上调催化输出。该反应由减数分裂I期间与MAPK结合的抑制剂Isc10和减数分裂II期间与Smk1/Isc10结合的激活剂Ssp2控制。在减数分裂完成后，Isc10被降解，Smk1经历自磷酸化，产生控制孢子形成的高活性MAPK。Isc10如何抑制Smk1尚不清楚。在这里，我们使用细菌共表达/重构系统在Isc10的羧基末端定义了一个特异性抑制Smk1自磷酸化的结构域。然而，结合该结构域的Smk1能够磷酸化其他底物，并磷酸化丝氨酸97上Isc10的氨基末端一半。反过来，Isc10中磷酸化的基序抑制Smk1活性位点。这些数据表明，Isc10通过不同的机制抑制自磷酸化和底物的磷酸化。此外，我们证明Isc10可以抑制哺乳动物肠细胞激酶ICK1（也称为CILK1）的自磷酸化，表明其作用机制保守。这些发现定义了一类新的发育调节分子，可以阻止mapk和mapk样酶的自激活。
Many eukaryotic protein kinases are activated by the intramolecular autophosphorylation of activation loop residues. Smk1 is a meiosis-specific mitogen-activated protein kinase (MAPK) in yeast that autophosphorylates its activation loop tyrosine and thereby upregulates catalytic output. This reaction is controlled by an inhibitor, Isc10, that binds the MAPK during meiosis I and an activator, Ssp2, that binds Smk1/Isc10 during meiosis II. Upon completion of the meiotic divisions, Isc10 is degraded, and Smk1 undergoes autophosphorylation to generate the high activity form of the MAPK that controls spore formation. How Isc10 inhibits Smk1 is not clear. Here, we use a bacterial coexpression/reconstitution system to define a domain in the carboxy-terminal half of Isc10 that specifically inhibits Smk1 autophosphorylation. Nevertheless, Smk1 bound by this domain is able to phosphorylate other substrates, and it phosphorylates the amino-terminal half of Isc10 on serine 97. In turn, the phosphorylated motif in Isc10 inhibits the Smk1 active site. These data show that Isc10 inhibits autophosphorylation and the phosphorylation of substrates by separate mechanisms. Furthermore, we demonstrate Isc10 can inhibit the autophosphorylation of the mammalian intestinal cell kinase ICK1 (also known as CILK1), suggesting a conserved mechanism of action. These findings define a novel class of developmentally regulated molecules that prevent the self-activation of MAPKs and MAPK-like enzymes.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
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Hassabis D
影响因子：
56.9
作者：
Ge, BX;Gram, H;Han, JH
通讯作者：
Han, JH
影响因子：
4.8
作者：
Grimsey, Neil J.;Lin, Ying;Trejo, JoAnn
通讯作者：
Trejo, JoAnn
影响因子：
16.8
作者：
De Nicola, Gian Felice;Martin, Eva Denise;Chaikuad, Apirat;Bassi, Rekha;Clark, James;Martino, Luigi;Verma, Sharwari;Sicard, Pierre;Tata, Renee;Atkinson, R. Andrew;Knapp, Stefan;Conte, Maria R.;Marber, Michael S.
通讯作者：
Marber, Michael S.
影响因子：
4.1
作者：
HER, JH;LAKHANI, S;WEBER, MJ
通讯作者：
WEBER, MJ