中国农业大学等最新《PNAS》文章

　　生物通报道：来自美Jewish国立医疗研究中心（National Jewish Medical and Research Center），中国农业大学生物科学学院，霍华德休斯医学院，清华大学与中国医学科学院（中国协和医科大学）医学分子生物学国家重点实验室（National Key Laboratory of Medical Molecular Biology）等处的研究人员通过获得JHDM3A催化核心与甲基化H3K36多肽底物的复合结晶结构，加深了对组蛋白去甲基化的机制及特异性的了解。这一研究成果公布在《美国国家科学院院刊》（PNAS）网络版上。

文章的通讯作者是来自Jewish国立医疗研究中心的John Kappler，及张公义（Gongyi Zhang，音译）博士，后者早年于中科院生物物理所获得博士学位。

原文摘要：
Published online before print June 13, 2007
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0704525104
Structural basis of the recognition of a methylated histone tail by JMJD2A
[Abstract]

在基因组中除了DNA和RNA序列以外，还有许多调控基因的信息，它们虽然本身不改变基因的序列，但是可以通过基因修饰，蛋白质与蛋白质、DNA和其它分子的相互作用，而影响和调节遗传基因的功能和特性，并且通过细胞分裂和增殖周期影响遗传，科学家们将这一种遗传方式称为表观遗传学（epigenetics）。

组蛋白甲基化是表观遗传修饰方式中的一种，参与了异染色质的形成、基因印记、染色体失活和基因转录调控等，其中jumonji C (JmjC)位点是介导组蛋白赖氨酸去甲基化的一个催化位点。

在这篇文章中，研究人员获得了JHDM3A（jumonji C (JmjC)-domain-containing histone demethylase 3A，也称为JMJD2A）催化核心与甲基化H3K36多肽底物的复合结晶结构，从中研究人员发现JMJD2A和多肽之间的相互作用是这个酶和多肽的主要部分。另外多肽结合的特异性主要是由多肽的的初级结构决定的，也就解释了JMJD2A对于H3K8和H3K36具有特异性，而对其它甲基化残基，譬如H3K27没有这种特异性。

除此之外，研究人员还发现一种特殊的甲基化基团的特异性是受到多因素影响的，比如酶催化中心的空间，及静电环境等。这些都有助于我们加深对组蛋白去甲基化的机制及特异性的了解。
（生物通：万纹）

附：
Gongyi Zhang, Ph.D. 

Primary Department: Immunology, National Jewish Medical and Research Center
Education: Ph.D. 1993, Institute of Biophysics, Chinese Academy of Sciences, Beijing.
Email: [e-mail]

Research Program:

The laboratory of Dr. Zhang studies structural and functional relations of macromolecules, which play crucial roles in variety of biological processes. The following are several areas that we are currently focusing on.

1. Structural and functional characterization of JmjC containing histone demethylases.

Covalent modifications of histone proteins, essential regulators of the activity of genes in eukaryotic cells, remodel the chromatin structure via a variety of enzymatic reactions. The reversible processes of some modifications, such as acetylation and deacetylation, are well characterized. Whether methylation and demethylation reversibly contribute to gene regulation, however, remains controversial. Recent studies have shown that methylation and demethylation are universally used to posttranslationally modify histones for the regulation of gene activity. In addition to LSD1, a nuclear amine oxidase homolog, which was found to function as a histone lysine demethylase, it was found that some JmjC domain-containing proteins are histone demethylases. Specifically, in collaboration with Dr. Yang Shi’s group at Harvard university, we found that members of the JMJD2 protein family are histone demethylases that act on trimethyl groups of H3-K9 and H3-K36. Moreover, some members of this family also have activity for dimethyl groups. To understand the relationships between the structures and functions of these proteins, we have determined the structure of the catalytic core of the JMJD2A protein. From this structure, several novel structure features were revealed, such as the novel JmjN domain, the JmjC domain, the C-terminal domain, and a zinc finger motif. These unique structural features create a potential catalytic center. The structure also revealed a characteristic signature motif, which includes structural determinants for cofactors such as Fe(II) and -ketoglutarate, a hallmark of non-heme containing oxygenases.

2. Characterization of Novel signal transduction mechanism through TALL-1 and its cognate receptors.

Trimer is the only functional unit for ligands of TNF family members, and trimer ligands recruit randomly distributed receptors on the membrane so as to trigger the down stream signal transduction. The novel virus-like structures of sTALL-1 with and without its cognate receptors determined in my lab are not consisted with the above common and well accepted theories. The sTALL-1 structure showed that sTALL-1 prefers existing at form of clustering with 20 trimers or 60 monomers through a novel “flap” region in vitro or vivo. Furthermore, the clustering state is the only functional unit. Structures of sTALL-1 with its cognate receptors, BCMA, BAFF-R, and TACI, showed that there are not only novel structural modules in these receptors (such as D2, X2, and others) but also novel interaction modes between ligand and receptors. These structure and interaction novelty underling novel signal transduction mechanism. Furthermore, structural modeling work on TALL-2/APRIL revealed a unique structural basis that distinglishes between sTALL-1 and APRIL for BAFF-R. 

3. Structural and functional analysis of a new transcription family members.

Staphylococcus aureus (S. aureus) is a major pathogen in nosocomial bacteremia, generally accounting for ~15-20% of these bacteremic episodes. The expression of microbial virulence factors in S. aureus is a complex process that involves interactions among many gene products. Many of these virulence genes are regulated by global regulatory systems. One of them is the sar (staphylococcal accessory regulator) locus, which not only regulates the agr locus (accessory global regulator, containing protein or peptides, AgrA, AgrB, AgrC, and AgrD), but also directly controls the expression of several putative virulence determinants (e.g. hemolysins, fibrinogen and fibronectin binding proteins). A major transcription factor family plays pivotal roles in the regulation of the sar system, it is called SarA, We have determined several structures of fthe family members, SarR, SarA, and SarS etc. From these four structures, we further classified them in three sub families, SarA motif including SarA and SarR, which functions as homodime, SarS motif, which functions as monomer but contains two homolog SarA motif (as heterodimer), and RAT motif, which functions as homodimer, but contains additional helix bundle at its c-terminal.

Selected Publications:

Chen Z, Zang J, Whetstine J, Hong X, Davrazou F, Kutateladze TG, Simpson M, Mao Q, Pan CH, Dai S, Hagman J, Hansen K, Shi Y, Zhang G. Structural insights into histone demethylation by JMJD2 family members. Cell. 2006 May 19;125(4):691-702. Epub 2006 May 4. 
Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M, Shi Y. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell. 2006 May 5;125(3):467-81. Epub 2006 Apr 6. 
Liu Y, Manna AC, Pan CH, Kriksunov IA, Thiel DJ, Cheung AL, Zhang G. Structural and function analyses of the global regulatory protein SarA from Staphylococcus aureus. Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2392-7. Epub 2006 Feb 2. 
Zhang G. Tumor necrosis factor family ligand-receptor binding. Curr Opin Struct Biol. 2004 Apr;14(2):154-60. 
Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, Pan CH, Martin WE, Murphy RC, Shu HB, Dai S, Zhang G. Ligand-receptor binding revealed by the TNF family member TALL-1. Nature. 2003 May 1;423(6935):49-56. 
Liu Y, Xu L, Opalka N, Kappler J, Shu HB, Zhang G. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family ligands. Cell. 2002 Feb 8;108(3):383-94. 
Cheung AL, Zhang. Are the structures of SarA and SarR similar? Trends Microbiol. 2001 Dec;9(12):570-3. 
Liu Y, Manna A, Li R, Martin WE, Murphy RC, Cheung AL, Zhang G. Crystal structure of the SarR protein from Staphylococcus aureus. Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6877-82. Epub 2001 May 29. 
Zhang G, Campbell EA, Minakhin L, Richter C, Severinov K, Darst SA. Crystal structure of Thermus aquaticus core RNA polymerase at 3.3 A resolution. Cell. 1999 Sep 17;98(6):811-24. 
Zhang G, Darst SA. Structure of the Escherichia coli RNA polymerase alpha subunit amino-terminal domain. Science. 1998 Jul 10;281(5374):262-6. 
Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997 Mar 20;386(6622):247-53. 
Zhang G, Kazanietz MG, Blumberg PM, Hurley JH. Crystal structure of the cys2 activator-binding domain of protein kinase C delta in complex with phorbol ester. Cell. 1995 Jun 16;81(6):917-24.