Eswaran Jeyanthy, Bernad Antonio, Ligos Jose M, Guinea Barbara, Debreczeni Judit E, Sobott Frank, Parker Sirlester A, Najmanovich Rafael, Turk Benjamin E, Knapp Stefan
Structural Genomics Consortium, Botnar Research Centre, University of Oxford, Oxford, United Kingdom.
Structure. 2008 Jan;16(1):115-24. doi: 10.1016/j.str.2007.10.026.
The activation segment of protein kinases is structurally highly conserved and central to regulation of kinase activation. Here we report an atypical activation segment architecture in human MPSK1 comprising a beta sheet and a large alpha-helical insertion. Sequence comparisons suggested that similar activation segments exist in all members of the MPSK1 family and in MAST kinases. The consequence of this nonclassical activation segment on substrate recognition was studied using peptide library screens that revealed a preferred substrate sequence of X-X-P/V/I-phi-H/Y-T*-N/G-X-X-X (phi is an aliphatic residue). In addition, we identified the GTPase DRG1 as an MPSK1 interaction partner and specific substrate. The interaction domain in DRG1 was mapped to the N terminus, leading to recruitment and phosphorylation at Thr100 within the GTPase domain. The presented data reveal an atypical kinase structural motif and suggest a role of MPSK1 regulating DRG1, a GTPase involved in regulation of cellular growth.
蛋白激酶的激活片段在结构上高度保守，是激酶激活调控的核心。在此，我们报道了人类MPSK1中一种非典型的激活片段结构，它由一个β折叠和一个大的α螺旋插入组成。序列比较表明，MPSK1家族的所有成员以及MAST激酶中都存在类似的激活片段。使用肽库筛选研究了这种非经典激活片段对底物识别的影响，结果揭示了一个优选的底物序列X-X-P/V/I-φ-H/Y-T*-N/G-X-X-X（φ为脂肪族残基）。此外，我们鉴定出GTP酶DRG1是MPSK1的相互作用伙伴和特异性底物。DRG1中的相互作用结构域定位于N端，导致在GTP酶结构域内的Thr100处募集并磷酸化。所呈现的数据揭示了一种非典型的激酶结构基序，并提示MPSK1在调控DRG1（一种参与细胞生长调控的GTP酶）中发挥作用。
