2009年9月1日，清華大學(xué)施一公教授團(tuán)隊(duì)在美國(guó)PNAS雜志發(fā)表了題為“Cleavage of RseA by RseP requires a carboxyl-terminal hydrophobic amino acid following DegS cleavage”的文章,。
細(xì)胞外環(huán)境變化會(huì)通過(guò)一系列的信號(hào)轉(zhuǎn)導(dǎo)通路最終影響細(xì)胞內(nèi)部的代謝水平,，受控膜內(nèi)蛋白水解（Regulated intramembrane proteolysis,RIP）是近年發(fā)現(xiàn)的一種調(diào)節(jié)膜蛋白內(nèi)外信號(hào)傳導(dǎo)的機(jī)制。S2P是一種膜整合金屬蛋白酶,，其底物也是膜蛋白,。S2P切割膜底物，使之釋放被細(xì)胞膜束縛住的信號(hào)分子，從而將信號(hào)傳導(dǎo)至細(xì)胞核中,。但是令人費(fèi)解的是,，S2P對(duì)底物的水解必須依賴另一種蛋白酶S1P對(duì)底物進(jìn)行第一步切割之后才能發(fā)揮作用，這其中的機(jī)理尚不明確,。
施一公教授領(lǐng)導(dǎo)的清華團(tuán)隊(duì)在9月初的《美國(guó)科學(xué)院院刊》（PNAS）發(fā)表文章,，通過(guò)生物化學(xué)和結(jié)構(gòu)生物學(xué)的手段對(duì)這一問(wèn)題進(jìn)行了解答，發(fā)現(xiàn)底物被S1P水解后暴露出的C端氨基酸對(duì)S2P的活性的調(diào)節(jié)發(fā)揮了重大的作用,。本篇文章被選為此期雜志的封面介紹文章,，美國(guó)西南醫(yī)學(xué)中心神經(jīng)生物系的兩位科學(xué)家為此研究成果撰寫的一篇評(píng)論同時(shí)發(fā)表在該雜志上，對(duì)這項(xiàng)工作進(jìn)行高度贊譽(yù),，認(rèn)為它為理解包括與老年癡呆癥密切相關(guān)的gamma-Secretase在內(nèi)的受控膜內(nèi)蛋白水解的調(diào)節(jié)機(jī)理作出了重要突破,。
值得一提的是，此工作在施一公老師和王佳偉老師的指導(dǎo)下,，全部為清華大學(xué)一年級(jí)的研究生和高年級(jí)本科生完成,。（生物谷Bioon.com）
生物谷推薦原始出處：
PNAS September 1, 2009 vol. 106 no. 35 14837-14842
Cleavage of RseA by RseP requires a carboxyl-terminal hydrophobic amino acid following DegS cleavage
Xiaochun Lia, Boyuan Wangb, Lihui Fenga, Hui Kanga, Yang Qia, Jiawei Wanga and Yigong Shia,b,1
aMinistry of Education Protein Science Laboratory and Center for Structural Biology, Department of Biological Sciences and Biotechnology, and
bSchool of Medicine, Tsinghua University, Beijing 100084, China
Regulated intramembrane proteolysis (RIP) by the Site-2 protease (S2P) results in the release of a transmembrane signaling protein. Curiously, however, S2P cleavage must be preceded by the action of the Site-1 protease (S1P). To decipher the underlying mechanism, we reconstituted sequential, in vitro cleavages of the Escherichia coli transmembrane protein RseA by DegS (S1P) and RseP (S2P). After DegS cleavage, the newly exposed carboxyl-terminal residue Val-148 of RseA plays an essential role for RseP cleavage, and its mutation to charged or dissimilar amino acids crippled the Site-2 cleavage. By contrast, the identity of residues 146 and 147 of RseA has no impact on Site-2 cleavage. These results explain why Site-1 cleavage must precede Site-2 cleavage. Structural analysis reveals that the putative peptide-binding groove in the second, but not the first, PDZ domain of RseP is poised for binding to a single hydrophobic amino acid. These observations suggest that after DegS cleavage, the newly exposed carboxyl terminus of RseA may facilitate Site-2 cleavage through direct interaction with the PDZ domain.
