徐华强研究组连发Science，PNAS文章

早年毕业于清华大学的徐华强（H. Eric Xu）教授现任美国Van Andel研究所结构科学与药物发现中心主任，2009年入选国家****，近期其研究组又与美国文安徳研究所Karsten Melcher、上海植生所与普渡大学的朱健康教授研究组合作，接连在Science Signaling和PNAS上发表了ABA信号通路调控机制的最新发现。

　　

生物通报道：早年毕业于清华大学的徐华强（H. Eric Xu）教授现任美国Van Andel研究所结构科学与药物发现中心主任，2009年入选国家****，兼任中国科学院上海药物研究所研究员。其研究组主要从事膜受体和核受体转换的分子结构特点与功能关系研究，获得多项原创性发现，近期这一研究组又与美国文安徳研究所Karsten Melcher、上海植生所与普渡大学的朱健康教授研究组合作，接连在Science Signaling和PNAS上发表了ABA信号通路调控机制的最新发现。

脱落酸信号通路是通过受体调节的激酶和磷酸化酶，从而控制下游的作用蛋白。但长期以来ABA的受体是什么，一直是一个存有颇多争议有待解决的关键科学问题。在2009年，ABA受体的发现及其结构的鉴定被Science杂志评为了当年度十大科学发现之一。其中部分结构生物学工作来自于徐华强与朱健康课题组的合作研究。

ABA的信号通路是通过受体激活下游激酶的，在没有ABA的情况下，激酶是被磷酸化酶抑制的。此次发表的两篇文章分别解决了激酶如何被抑制以及如何被激活的两个关键科学问题。

在“Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response”这篇文章中，研究人员报道了激酶和磷酸酶的复合体结构，从中发现激酶与ABA受体对磷酸化酶的识别有惊人的相似性。ABA受体的作用位点是在PP2C的活性中心。激酶和磷酸酶的复合体结构揭示了激酶的活性中心与PP2C的活性中心相互对接，从而模拟了受体-PP2C的相互作用。这些结构生物学的研究结论提出了一个简单的新机制，即耦合的ABA受体能直接抑制磷酸化酶并激活激酶。同时，这也揭示了激酶-磷酸化酶通过催化位点的相互作用而进行彼此调控的新法则。

而在“Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases”这篇文章中，研究人员报道了调控ABA信号通路激酶的自身激活机制。通常激酶要通过上游激活因子被激活，而调控ABA的激酶则不同，它具有高水平的自我激活能力。研究人员的结构发现，调节ABA的激酶具有一个特有的螺旋结构来固定激酶的三维结构，从而维持激酶的自我磷酸化活性。结合ABA受体—PP2C复合体结构，该研究详实地解析了ABA激素如何抑制PP2C从而激活调节aba信号通路的激酶，从而为ABA信号通路的核心结构提供一个完整的解析。

目前，世界范围内淡水资源的缺乏已成为一个不容忽视的问题，而农业用水量高达淡水资源的70%，淡水资源的匮乏业已成为遏制农业产量的最主要因素。因此，ABA信号通路的研究一直是植物科学领域的一大热点。ABA信号通路的研究以及ABA类似物的发现将有助于推进农作物的基因工程及抗旱、抗盐的药物发现，对于缓解我国农业用水的困境有着极为重要的意义。

原文摘要：

Structural basis for basal activity and autoactivation of abscisic acid (ABA) signaling SnRK2 kinases

Abscisic acid (ABA) is an essential hormone that controls plant growth, development, and responses to abiotic stresses. Central for ABA signaling is the ABA-mediated autoactivation of three monomeric Snf1-related kinases (SnRK2.2, -2.3, and -2.6). In the absence of ABA, SnRK2s are kept in an inactive state by forming physical complexes with type 2C protein phosphatases (PP2Cs). Upon relief of this inhibition, SnRK2 kinases can autoactivate through unknown mechanisms. Here, we report the crystal structures of full-length Arabidopsis thaliana SnRK2.3 and SnRK2.6 at 1.9- and 2.3-Å resolution, respectively. The structures, in combination with biochemical studies, reveal a two-step mechanism of intramolecular kinase activation that resembles the intermolecular activation of cyclin-dependent kinases. First, release of inhibition by PP2C allows the SnRK2s to become partially active because of an intramolecular stabilization of the catalytic domain by a conserved helix in the kinase regulatory domain. This stabilization enables SnRK2s to gain full activity by activation loop autophosphorylation. Autophosphorylation is more efficient in SnRK2.6, which has higher stability than SnRK2.3 and has well-structured activation loop phosphate acceptor sites that are positioned next to the catalytic site. Together, these data provide a structural framework that links ABA-mediated release of PP2C inhibition to activation of SnRK2 kinases.


Identification of a Lysosomal Pathway That Modulates Glucocorticoid Signaling and the Inflammatory Response

The antimalaria drug chloroquine has been used as an anti-inflammatory agent for treating systemic lupus erythematosus and rheumatoid arthritis. We report that chloroquine promoted the transrepression of proinflammatory cytokines by the glucocorticoid receptor (GR). In a mouse collagen-induced arthritis model, chloroquine enhanced the therapeutic effects of glucocorticoid treatment. By inhibiting lysosome function, chloroquine synergistically activated glucocorticoid signaling. Lysosomal inhibition by either bafilomycin A1 (an inhibitor of the vacuolar adenosine triphosphatase) or knockdown of transcription factor EB (TFEB, a master activator of lysosomal biogenesis) mimicked the effects of chloroquine. The abundance of the GR, as well as that of the androgen receptor and estrogen receptor, correlated with changes in lysosomal biogenesis. Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors.