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Hans Journal of Computational Biology
Vol.2 No.2(2012), Article ID:2927,15 pages DOI:10.4236/HJCB.2012.22002

Bioinformatics Analysis of Two-Component Singal Transduction Systems of Xanthomonas

Fen Hu, Xia Zou, Han Mei, Qing Tang, Jin He*

State Key Laboratory of Agricultural Microbiology, College of Life Science and Technology, Huazhong Agricultural University, Wuhan

Email: *hejin@mail.hzau.edu.cn

Received: Jun. 10th, 2012; revised: Jun. 24th, 2012; accepted: Jun. 27th, 2012

ABSTRACT:

Two-component signal transduction systems (TCSs) represent the dominant sense-response mechanisms to regulate a wide array of physiological pathways in prokaryotes. TCSs can regulate the majority of physiological processes, including bacterial growth, chemotaxis, osmoregulation, sporulation, biosynthesis of secondary metabolites, virulence of pathogens, biofilm formation, etc. In this paper, we predicted all the TCS genes and comprehensively analyzed their biological functions in the whole genomes of 8 Xanthomonas strains. We depicted a systematic classification of these proteins, then analyzed their structures and putative biological functions by sequence alignment, multiple sequence alignment, phylogenetic tree analysis, Hidden Markov Model (HMM), secondary structure prediction etc, and finally constructed the regulatory networks in which some TCSs involved. Our research revealed the relationship between TCS genes and the pathogenicity of Xanthomonas, as well as the possible evolutionary relationship; furthermore, our results could lay the foundation for exploring new drug targets.

Keywords: Xanthomonas; Two-Component System (TCS); Regulatory Network; Pathogenicity; Bioinformatics

黄单胞菌双组分信号转导系统的生物信息学分析

胡  芬,邹  霞,梅  寒,唐  清,何  进*

华中农业大学生命科学技术学院,农业微生物学国家重点实验室,武汉

Email: *hejin@mail.hzau.edu.cn

摘 要:

双组分信号转导系统是原核生物感知与响应刺激的重要代谢调节机制,广泛参与细菌的各种生理生化反应。本文采用生物信息学手段,利用多序列对比、系统进化树分析、跨膜区分析、二级结构预测等,对已完成全基因组测序的8株黄单胞菌中的双组分进行系统分类、结构分析和功能预测,初步构建了部分双组分信号转导系统的调控网络关系图,揭示了黄单胞菌致病性与双组份之间的联系,并初步阐明了黄单胞菌种间的进化关系,同时也为寻找新的药物靶标奠定了基础。

收稿日期:2012年6月10日;修回日期:2012年6月24日;录用日期:2012年6月27日

关键词:黄单胞菌;双组分系统;调控网络;致病性;生物信息学

1. 引言

黄单胞菌属(Xanthomonas)属于变形菌门,黄单胞菌科,革兰氏阴性菌。菌体呈短杆状,多单生,少双生,单端极生鞭毛,专性好氧[1]。黄单胞菌属种类繁多,《伯杰氏系统细菌学手册》(第二版)收录了20个黄单胞菌种,70个分类地位已经确定的和70个分类地位尚不确定的致病变种[2]

黄单胞菌属大部分成员为致病菌,且致病性非常多样,引起的植物病害遍布全世界,病害症状多为叶斑、叶枯、萎蔫、溃疡等。目前,由黄单胞菌引起的水稻白叶枯病、禾谷黑径病、柑橘溃疡病、辣椒斑点病、十字花科植物黑腐病和棉花角斑病等对农业生产造成了巨大的危害。因此,深入了解其致病机理对黄单胞菌的防治有深远的意义。

双组分信号转导系统(two-component signal transduction system,TCS)是广泛存在于原核生物和真核生物中的一种信号调节系统。在细菌中,该系统可以对环境的变化做出相应的反应,直接或间接地接收且传递生物信号,以调节相关基因的表达。典型的TCS由组氨酸蛋白激酶(histidine protein kinase,HK)和响应调节蛋白(response regulator protein,RR)组成。HK的输入结构域感应外界条件刺激,使其传递结构域的组氨酸(His)残基自磷酸化,随后,再将磷酸基团转移到RR接受结构域的天冬氨酸(Asp)残基上,磷酸化的RR抑制或激活下游基因的转录[3]。原核生物中的TCS常以简单的“HK-RR”形式存在。但是,某些组氨酸激酶除了含有输入结构域和传递结构域外,其C端还融合了一个含有Asp残基的接受域,这种组氨酸激酶被称为杂合型组氨酸激酶(hybrid histidine kinase,HY),真核生物大多拥有HY参与的多步骤磷酸传递的双组分信号系统[4]。在细菌中,TCS参与调节许多的生理生化过程,包括细菌的趋化性、蛋白质合成、营养物质同化、细胞运动、渗透压、群体感应、感受性和致病性、生物膜和群体感应等[5]

目前,全基因组序列被测通的Xanthomonas属菌株共有8种,分别是水稻白叶枯病菌(Xanthomonas oryzae pv. oryzae, Xoo)MAFF311018菌株[6]、KACC10331菌株[7]和PXO99A菌株[8],野油菜黄单胞菌野油菜致病变种(Xanthomonas campestris pv. campestris, Xcc)8004菌株[9]、B100菌株[10]和ATCC33913菌株[11],柑橘溃疡黄单胞菌(Xanthomonas axonopodis pv. citri, Xac) 306菌株[11]以及番茄疮痂病菌(Xanthomonas campestris pv. vesicatoria, Xcv)85-10菌株[12]。本文采用生物信息学手段,从这8株菌中鉴定HK、RR和HY,对这些TCS组分进行系统分类、结构分析和功能预测,并初步构建了部分TCS的调控网络关系图。该研究为进一步揭示TCS的作用机制和开发药物靶标提供了重要的理论指导。

2. 材料与方法

2.1. 序列来源

Xoo KACC10331(GenBank accession NC006834.1)、Xoo MAFF311018(GenBank accession NC007705.1)、Xoo PXO99A(GenBank accession NC010717.1)、Xcc 8004(GenBank accession NC007086.1)、Xcc ATCC33913(GenBank accession NC003902.1)、Xcc B100(GenBank accession NC010688.1)、Xcv 85-10(GenBank accession NC007508.1)和Xac 306(GenBank accession NC005240.1)全基因组序列来自GenBank (www.ncbi.nih.gov/genomes/Bacteria);其基因组注释来自华中农业大学DIGAP (http://ibi.hzau.edu.cn/digap/phytopathogens.php)。

2.2. TCS预测、多重序列比对及进化树构建

根据上述8株菌的基因组注释搜寻可能的HK、RR和HY,利用Pfam中HK和RR的保守结构域HATPase_c(Pfam02518)和Response_reg(Pfam00072)对结果进行筛选,最后通过NCBI的BLASTp程序确认TCS的各组分;蛋白质序列比对采用ClustalW软件进行;进化树利用同源基因非同义突变的相邻–连接分析,采用ClustalW和Mega(Molecular Evolutionary Genetics Analysis)Vision 4.1软件进行构建,分析结果进行bootstrap验证,重复次数设置为1000。

2.3. 序列相似性分析和功能域分析

利用Pfam和BLASTp进行保守结构域分析,用ClustalW分析序列的相似性,TMHMM Server 2.0 (http://www.cbs.dtu.dk/services/TMHMM-2.0)对TCS跨膜结构域进行预测,结合文献报道,预测TCS各组分的功能,并在此基础上构建黄单胞菌TCS信号转导网络。

3. 结果

3.1. 黄单胞菌双组分系统各组分的鉴定

对黄单胞菌株全基因组序列进行生物信息学分析,我们一共预测出671个编码TCS各组分(包括HK、RR和HY)的基因,分布特征如表1所示,详细信息见附表1~8。可见,TCS基因均匀地分布于这8株Xanthomonas基因组中,且在不同菌株中TCS的排列顺序和相对位置也相似,如图1。

Table 1. General features of TCSs in the 8 genomes of Xanthomonas

表1. 黄单胞菌中双组分信号转导系统的特征

Figure 1. Distributions of TCSs in the chromosomes of the 8 Xanthomonas strains

图1. 双组分系统在八株黄单胞菌基因组中的分布

在这8株菌的671个TCS基因中,每株菌HK的数量在21~37之间、RR的数量在28~57之间、HY的数量在8~20之间,可见各个菌株中的TCS组分的数量波动范围并不大。另外一方面,成对的HK/RR的数量也相差不大,平均为23对。虽然TCS基因在基因组中所占的比例非常小,最高的仅为3.09%,但TCS在细菌的整个生理生化过程中却起着重要的作用,因此,进一步深入了解TCS的调控机制是十分必要的。

3.2. 黄单胞菌属双组分系统各组分进化图

为了更好地了解TCS编码基因之间的相互联系,我们分别构建了各组分(HK、RR、HY)在不同菌中的进化树,如图2~4。根据氨基酸序列相似性程度,结合功能预测(见表2),我们将具有高相似性的一类蛋白归于一个群(cluster)。分析结果显示黄单胞菌的TCS大致可以分为16个群,每一个群代表一对同源的TCS,它们分别是:ExsG/ExsF、RpfC/RpfG、AlgZ/AlgR、ColS/ColR、PhoQ/PhoP、TctD/TctE、KdpD/KdpE、YgiY/YgiX、LytS/LytT、CreC/CreB、NtrB/NtrC、CvgS/CvgY、RegS/RegR、PilS/PilR、BaeS/BaeR、PhoR/PhoB。

HY进化树主要包含4个类群:StyS、FixL、TorS、RpfC。其中,RpfC主要参与对细胞毒力的和第二信使的调控,部分是经过HY蛋白多步磷酸传递发挥作用的,此调节方式为信号转导调节提供了多个调控位点,提高了对信号感应的精确性,是细菌不断适应环境变化的体现。

3.3. 黄单胞菌属双组分系统功能预测

根据黄单胞菌TCS各组分的保守结构域和在基因组中的相对位置,我们发现了36对不同的TCS。根据序列相似性分析和相关文献的报道,我们预测了黄单胞菌中一些双组分调节系统的功能。表2是8株黄单胞菌(编号A到H)双组分功能预测结果,序列比对结果是以8株菌中氨基酸水平最小id%(Identities)为基准。结果显示,在功能上,TCS对细菌的生理调节涉及多个方面,主要包括细胞壁的合成和调节(如LiaS/LiaR、VraS/VraR、LiaS/LiaR、LytS/LytT)、金属离子的调节(如ZarS/ZarR、CusS/CusR)、物质的代谢(AtoS/AtoR、GlnL/GlnG、CreC/CreB)、细菌的运动性(QseC/QseB)等。另外,调控碱性磷酸酶合成的PhoQ/PhoP、鞭毛运动的QseC/QseB、锌离子代谢的ZarS/ZarR等双组分系统都存在于这8株菌中,且数量较其他双组分系统多,说明这几对双组分可能是黄单胞菌所必须的调节系统。另外,TCS在分布上也存在着差异,例如,PhoQ/PhoP、QseC/QseB、ZarS/ZarR、RpfC/RpfG、KdpE/KdpD、GlnL/GlnG等基本存在于每一株黄单胞菌中;而PdtaS/PdtaR、EnvZ/OmpR、DesK/DesR、VraS/VraR这几对TCS在Xoo 10331、Xoo 311018、Xoo 99A中均不存在,ArlS/ArlR、NarQ/NarP只存在于Xcc 100菌株中。这些结果为TCS基因在黄单胞菌不同菌株间水平转移提供了证据。

Figure 2. Phylogenetic trees of HYs from Xoo 10331, Xoo 311018, Xoo 99A, Xcc 33913, Xcc 8004, Xcc B100, Xcv and Xac

图2. 八株黄单胞菌中杂合蛋白(HY)的进化树

Figure 3. Phylogenetic trees of HKs from Xoo 10331, Xoo 311018, Xoo 99A, Xcc 33913, Xcc 8004, Xcc B100, Xcv and Xac

图3. 八株黄单胞菌中组氨酸蛋白激酶(HK)的进化树

3.4. 黄单胞菌属双组分系统信号调控网络

我们在预测8株Xanthomonas菌TCS功能的基础上,结合相应的数据库和软件[37,38],构建出黄单胞菌中部分TCS的调控网络(图5)。从网络图中可以看到,当HK和RR相互作用时,存在“一对多,多对一”的信号交谈(cross-talk)现象,形成了更复杂的TCS调控网络,从而能快速、准确地对细胞内外的各种信号刺激做出响应。

一方面,一个HK可以使多个RR发生磷酸化;同时,一个RR也可被多个HK磷酸化。例如,当黄单胞菌在低Ca2+和Mg2+离子的条件下,PhoR诱导PhoP的表达,从而调控下游基因phoPR的表达;而PhoP又可以被RaxH/RaxR这对双组分负调控,从而响应外界低金属离子浓度[39]。又如,黄单胞菌在感受到群体感应信号(DSF)时,会促使双组分RpfC/RpfF调控下游基因的表达,而RpfC受另一双组分RpfG

Figure 4. Phylogenetic trees of RRs from Xoo 10331, Xoo 311018, Xoo 99A, Xcc 33913, Xcc 8004, Xcc B100, Xcv and Xac

图4. 八株黄单胞菌中响应调节蛋白(RR)的进化树

的调控;同时,RpfG又会受到双组分RavS/RavR的负调控[40]

另一方面,同一生理活动可以被多对TCS同时调控;同时,一对TCS也可以同时调控多种生理活动。例如,细菌在应对DSF情况下,感应激酶蛋白RpfC使对应的响应调节蛋白RpfG磷酸化从而调节下游基因;同时细胞内另一双组分NtrB/NtrC也会对这一外界刺激进行响应[40]。又如,有报道指出,在野油菜黄单胞菌ATCC33913中,响应调节蛋白VgrR是一个全局调节因子,将vgrR突变后,细菌的致病性、渗透性、细胞生长和耐盐性等多种生命调节活动均会受到影响。

另外,在HY参与的TCS信号转导系统中,细胞可以响应多步磷酸传递的信号,从而应对外界环境的变化[41]

Table 2. The similarity and function prediction of TCSs of the 8 Xanthomonas strains

表2. Xanthomonas八株菌中的TCS相似性分析和功能预测

The arrows and T-formed lines show positive and negative transcriptional regulation, respectively. Green letters indicate environmental stimuli. The red and black letters represent HKs and RRs, respectively. Circles represent genes induced under anaerobic conditions. Blue represent genes involved in TCSs, purple represent proteins involved in TCS.

Figure 5. TCS regulatory network in Xanthomonas

图5. 黄单胞菌TCS调控网络

4. 讨论

通过对已完成测序的8株黄单胞菌的TCS进行的生物信息学分析,我们发现这些TCS基因在基因组中均匀分布。水稻黄单胞菌属的三株菌较其他菌株有着较小的基因组[42],其所包含的TCS数目也明显少于其他菌株(表1),特别是Xoo PXO99A。说明缺少的TCS组分对水稻黄单胞菌是非必需的,这可能是由于水稻被长期养殖并得到驯化而对其产生的进化选择。

典型的HK包含四个保守的N、D、F和G-Box的结构域[43],但是并非所有的HK包含所有的保守结构域。HK结构域的相对多变可能是由于其感知不断变化的外界刺激而发生的进化,由于黄单胞菌不同亚种之间所侵染的寄主植物不同,因此其感知的外界刺激也有所差别。至于RR,大部分RR在N-末端的结构域是非常保守的。结合图5中HK和RR的相互成对现象,我们认为在进化过程中,磷酸传递这种不同基因之间的作用形式被保留下来了。

研究表明,TCS也涉及一些致病菌毒力因子的表达调控[44],但是大多数TCS的生理功能并没有被完全揭示。作用机制相似的TCS广泛存在于各类微生物中并调控多种重要生物学功能,因此被认为是潜在的药物靶标。有研究者已经针对TCS找到一类与ATP竞争以阻断HK激酶活性的抑制物[45,46]

本文全局性地概括了黄单胞菌TCS的种类、功能、及其在基因组的分布,并构建了其调控网络,为深入研究TCS对黄单胞菌的生长、代谢以及毒力因子的表达调控奠定了基础;同时揭示了黄单胞菌致病性与TCS之间的联系,并初步阐明了黄单胞菌种间的进化关系。为寻找药物靶标以及防治黄单胞菌引起的病害提供了新的研究思路。

5. 致谢

本文由973项目(2010CB126105)、国家自然科学基金(31070065)和湖北省自然科学基金(2010CDB10003)资助。感谢王阶平博士对本文提出的建设性意见,硕士研究生王燕也对本文给予帮助。

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附录

Supplemental Table 1. Classification of two-component systems in Xanthomonas oryzae pv. oryzae KACC10331

附表1. Xanthomonas oryzae pv. oryzae KACC10331双组分系统分类

Supplemental Table 2. Classification of two-component systems in Xanthomonas oryzae pv. oryzae MAFF311018

附表2. Xanthomonas oryzae pv. oryzae MAFF311018双组分系统分类

Supplemental Table 3. Classification of two-component systems in Xanthomonas oryzae pv. oryzae PXO99A

附表3. Xanthomonas oryzae pv. oryzae PXO99A双组分系统分类

Supplemental Table 4. Classification of two-component systems in Xanthomonas campestris pv. campestris str. ATCC 33913

附表4. Xanthomonas campestris pv. campestris str. ATCC 33913双组分系统分类

Supplemental Table 5. Classification of two-component systems in Xanthomonas campestris pv. campestris str. 8004

附表5. Xanthomonas campestris pv. campestris str. 8004双组分系统分类

Supplemental Table 6. Classification of two-component systems in Xanthomonas campestris pv. campestris str. B100

附表6. Xanthomonas campestris pv. campestris str. B100双组分系统分类

Supplemental Table 7. Classification of two-component systems in Xanthomonas campestris pv. vesicatoria str. 85-10

附表7. Xanthomonas campestris pv. vesicatoria str. 85-10双组分系统分类

Supplemental Table 8. Classification of two-component systems in Xanthomonas axonopodis pv. citri str. 306

附表8. Xanthomonas axonopodis pv. citri str. 306双组分系统分类

NOTES

*通讯作者。

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