报告人：王志新院士、吴嘉炜教授
主持人：医学部主任 吴庆宇教授
报告时间：2015年5月25日（星期一）上午9：00
报告地点：独墅湖校区703号楼唐仲英血液学研究中心学术报告厅（3502-3504室）
报告主题1：Autoactivation mechanism of p21-activated protein kinases
The p21-activated kinases (PAKs) are serine/threonine protein kinases defined by their interactions with the small G proteins, and play important roles in diverse cellular processes. All PAKs (PAK1-6) contain an N-terminal regulatory domain and a C-terminal kinase domain. Full activation of PAKs requires autophosphorylation of a critical threonine/serine located in the activation loop of the kinase domain (Thr423 in PAK1 and Thr402 in PAK2). Specially, PAK2 is cleaved by caspase-3 in cell apoptosis and the resulted C-terminal fragment also undergoes autophosphorylation on Thr402 to get fully activated. We determined a series of crystal structures of the kinase domain of PAK1 and PAK2, in its phosphorylated or unphosphorylated status. These structures reveal three distinctive conformations of the unphosphorylated PAK kinase domain: the active conformation similar to the phosphorylated active kinase; the inactive conformation which can serve as a substrate to be phosphorylated by active kinases; and the pre-active conformation which is competent to undergo cis-autophosphorylation. Based on the structural information, we established a kinetic model to describe the autophosphorylation process of PAK kinase domain and conducted detailed enzyme kinetic assays to quantitatively estimate all microscopic kinetic constants. Together, these structural and kinetic studies uncover the molecular mechanism for the autoactivation of PAKs, in which the unphosphorylated kinase domain has an intrinsic ability to sample divered conformations to facilitate both cis- and trans-autophosphorylation.
报告人：王志新院士
报告主题2：Conserved Elements in Allosteric Regulation of AMP-activated Protein Kinase
The AMP-activated protein kinase (AMPK) acts as a master switch of anabolic and catabolic states by sensing the change in cellular levels of adenine nucleotides and regulating key metabolic pathways, and is thus a major drug target for obesity, type 2 diabetes and other metabolic disorders. AMPK is a heterotrimeric enzyme composed of the catalytic α-subunit and regulatory β- and γ-subunits and characterized by its ability able to undergo allosteric activation upon AMP binding to the γ-subunit. We provide lines of evidence showing that mammalian and yeast AMPKs possess a universally conserved autoinhibitory domain (AID). The AID domain binds to the ‘backside’ of its kinase domain and constrains the mobility of the prominent αC helix, hence resulting in an autoinhibited AMPK. We also determined the co-crystal structures of mammalian AMPK core fragments in complex with either two ATP or three AMP molecules, which exhibit significant conformational differences on the γ-subunit. Further structure-based biochemical analyses identify two nucleotide binding sites on the γ-subunit as the pivotal regulatory sites for AMPK allosteric activation. Recently, we identified two motifs within the α-subunit that respectively interact with two γ-subunit sites and are indispensable for AMPK activation by AMP. Together, these structural and mutational analyses demonstrate three conserved regulatory elements within the α-subunit and lead to a more complete understanding of the coordinated allosteric regulation of mammalian AMPK.
报告人：吴嘉炜教授
报告人简介：
王志新
清华大学生命科学学院 教授, 中科院院士
工作经历:
1977-1981 清华大学化学与化学工程系，助教
1988-1981 中国科学院生物物理研究所，副研究员
1989-1991 美国康乃尔大学化学系，博士后
1991-1993 美国北达哥他州立大学生物化学系，研究助理
1993-2003 中国科学院生物物理研究所，研究员
1995-1999 中国科学院生物物理研究所，副所长
1997-2003 北京生物大分子国家重点实验室，主任
1997 中国科学院，院士
1999-2003 中国科学院生物物理研究所，所长
1999 第三世界科学院，院士
2003至今 清华大学生命科学学院，教授
学术荣誉:
1990年获中国科学院自然科学奖一等奖
1993年获国家自然科学奖二等奖
1993年获中国科学院青年科学家奖一等奖
1994年获中国青年科学家奖
研究方向:
1. 酶的催化与调节动力学
2.蛋白质结构预测
吴嘉炜
清华大学生命科学学院 教授
工作经历：
1999-2003美国普林斯顿大学分子生物学系，博士后
2003- 清华大学生命科学学院（原生物科学与技术系），教授
学术荣誉：
2001年，全国百篇优秀博士学位论文
2003年，清华大学“百人计划”
2004年，国家杰出青年基金
2009年，邹承鲁奖励基金杰出研究论文
2011年，第八届中国青年女科学家
2012年，教育部“长江学者”特聘教授
2013年，第六届谈家桢生命科学奖创新奖
研究方向：
运用分子酶学、结构生物学方法研究：
1.糖脂代谢中关键蛋白的结构和功能
2.信号通路中激酶和磷酸酶的调控机制
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