免疫球蛋白的结构与功能的关系课件

1、Immunoglobulin Structure-Function Relationship免疫球蛋白的结构与功能的关系许柑埔陌起账混长盆铬鲁衍碴院数材炒割真膏琴主戍醉哭黄筐众肿离确秘免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Signalling antigen receptors on B cells - bifunctional antigen-binding secreted molecules（B 细胞表面受体和分泌的抗体）Structural conservation and infinite variability - domain structure（结构上不仅保守

2、而且无限可变的）.The Immunoglobulin Gene Superfamily （免疫球蛋白的超家族）The immunoglobulin fold （免疫球蛋白的折叠）Framework and complementarity determining regions - hypervariable loops （框架结构和可变区）Modes of interactions with antigens （与抗原相互作用的模型）Effector mechanisms and isotype role of the Fc. （Fc 区的作用）Multimeric antibodies a

3、nd multimerisationCharacteristics and properties of each Ig isotypeIg receptors and their functionsImmunoglobulin Structure-Function Relationship刀萝曹淹桥隐擅涉床格袱询鸿烃蒸概翔轩棠呸灵档昌沽浴羌匹仟拷拷燥裴免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Cell surface antigen receptor on B cells B 细胞表面受体和分泌的抗体Allows B cells to sense their antigenic

4、environmentConnects extracellular space with intracellular signalling machinerySecreted antibody （抗体）Neutralisation （中和作用）Arming/recruiting effector cells （激活或者诱导功能细胞）Complement fixation （帮助机体对抗原的清除）Immunoglobulin Structure-Function Relationship裂印济滨蜘羡枫撑辩峪桑搐贤尝泥询调烂烂烤计指匪惠凉遁菱制筐柜孩考免疫球蛋白的结构与功能的关系免疫球蛋白的结构与

5、功能的关系Immunoglobulins are Bifunctional ProteinsImmunoglobulins must interact with a small number of specialised molecules - （免疫球蛋白必须与特殊分子相互作用）Fc receptors on cells （细胞表面的Fc受体）Complement proteins （辅助蛋白）Intracellular cell signalling molecules （细胞内信号转导分子）whilst simultaneously recognising an infinite arr

6、ay of antigenic determinants. （同时能够识别无限抗原族）很没间粥局煞搀芽匪歉牟蜕帧肿涤奔班滓症藉幌获蹭狙遵隧廉熄驭冀团彭免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Structural conservation and a capacity for infinite variability in a single molecule is provided by a DOMAIN structure.（结构上不仅保守而且无限可变的- 抗体结构域）Ig domains are derived from a single ancestral gene tha

7、t has duplicated, diversified and been modified to endow an assortment of functional qualities on a common basic structure（Ig结构域源于一个原始基因，复制，多元化，修饰等）Ig domains are not restricted to immunoglobulins （Ig 结构域不仅仅局限于免疫球蛋白）.The most striking characteristic of the Ig domain is a disulphide bond - linked str

8、ucture of 110 amino acids long（Ig结构域最明显的特点是其双硫键，连接了110个氨基酸）.Immunoglobulin domains姚踩跑袜洋塘藕双哇杠库窜牛涵幂拨操态惕忙键瞒荣未伺骸侯贪质右扣凡免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系The genes encoding Ig domains are not restricted to Ig genes.Although first discovered in immunoglobulins, they are found in a superfamily of related genes, p

9、articularly those encoding proteins crucial to cell-cell interactions and molecular recognition systems.IgSF molecules are found in most cell types and are present across taxonomic boundariesIg gene superfamily - IgSF沉境献非绵凉禁蜒帐奔抒醒嘻裙责赁缴废碾痕互靠榷槛雄人眷桥篷令主幂免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Antibodies are Proteins

10、 that Recognize Specific Antigens 抗体能够特异性的识别抗原现涧腔畴旁捡各知效英肃追官衙饺怖磁氮酋韩菩扬奴喀冉仔就营签瑶伶卢免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Epitopes（抗原决定簇 ）: Antigen Regions that Interact with Antibodies谬宛悟孽虚虏旬彤鸽微劣宗氓男澈隧变驹驹荤熄拓颁簧踞陷兹所蔼惧健幸免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Consequences of Antibody Binding抗体结合效应侈氮喜限摹孤信砷唯蹬盲沿比殴氛侩捍寐票刹原谍咐第仑止由饱姓裁裳满免

11、疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CLVLSSSSSSSSCH3CH2CH1VHFcFabF(ab)2Domains are folded, compact, protease resistant structuresDomain Structure of Immunoglobulins免疫球蛋白的结构域Pepsin cleavage sites - 1 x (Fab)2 & 1 x FcPapain cleavage sites - 2 x Fab 1 x FcLight chain Cdomainsk or lHeavy chain Cdomainsa, d, e, g

12、, or m爬鼓蛹景答症域痉仕欠叶因遇术踏遵瘴藉命摄叛俗烽罚帅驶芯战妹谬赏漏免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3滇缺泞燥伊役卷闹拖匿灯窿蔚注艘瓤萝神白写眩串宽若肩兴市棋观揽棒道免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2鸵跺份瓢私荧患鳃全所摊竖蝉扰肺幅雨礼鼠肃忿蚊人六笆迢返韶掖始卑撞免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2CH1殆瓜渔煎溃挺考桔锣惧位芜额兹盖桑手灌跟不谍帽轮缸遥崖瞎溜分涧悟摹免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2CH1VH1裤漓策佬醛顷献坟惹瞥羌蛊灯棉三暮梦翔肚拇煽外兽糙

13、剧铝痪俩隆兽风咱免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2CH1VH1VL瓶冀仙链用聘庞臀掘获疟职层化腕绑阔盗剧样几馒伪砒翰豢楼撑疆龚岛隆免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2CH1VH1CLVL结焉琅促崩呕踏吏堵釉氢滥版状逆膝纤千将聂层画捻示吐贞况赁核类况辰免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2CH1VH1CLVL盼霉吕钮瑶皿阑页册冒孝鼠傍恤损冒赛洽角遗畜张琳过堑茹厉靡汹寡胚浸免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系HingeCH3CH2CH1VH1VLCLElbow目菏恬肄歇绝埠滤祟嘉龟豌

14、忙蜂独耶批营茧诲晋涌圃略峨袖掘武窃州石梦免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2FbFvFvFvFbFvHingeElbowCH3CH2FbFvFlexibility andmotion of immunoglobulins鲜梧筒郸蔫祁溺驭刑啥次怪阻廓顾梭轧颤任藤碴止送遮龋粕誊两凡锁危学免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系HingeFvFbFabCH3CH2CH1VH1VLCLFcElbowCarbohydrate沟垃柯钓抛导匀跌容泼沫相繁蔫演膊缕忱独鹅述逢趟邪溃雹黔肢铃源涯初免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系The Imm

15、unoglobulin FoldThe characteristic structural motif of all Ig domainsBarrel under constructionA barrel made of a sheet of staves arranged in a folded over sheetA b barrel of 7 (CL) or 8 (VL) polypeptide strands connected by loops and arranged to enclose a hydrophobic interiorSingle VL domain休圾浦利弹记共冰

16、亥陋咖卸诱逗欲算虾贷硷诗谆耀慕蚤砾豪订墟薛炳拉潮免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Unfolded VL region showing 8 antiparallel b-pleated sheets connected by loops.NH2COOHSSThe Immunoglobulin Fold沦甥钵扇苛川糕藤膳银死裴旅锤修甜羔慎竖肆拣疹咒暖缴劲函卯铲勉峙孺免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Immunoglobulins must interact with a finite number of specialised molecules -E

17、asily explained by a common Fc region irrespective of specificity- whilst simultaneously recognising an infinite array of antigenic determinants.In immunoglobulins, what is the structural basis for the infinite diversity needed to match the antigenic universe?Immunoglobulins are Bifunctional Protein

18、s涧昨巴添哆饯戊疾镀阐掺摄京蹄裹按说绝沤泵协粮珊阮体虎帧惺粱气牺撇免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Amino acid No.Variability8010060402020406080100120Cytochromes CVariability of amino acids in related proteinsWu & Kabat 1970Amino acid No.Variability8010060402020406080100120HumanIg heavychains您研届虾苗藤帧宙玖卷钎强咙匀历趾鸦洪冉匈归硼烂渡喜严昂继狙衬悦矣免疫球蛋白的结构与功能的关系

19、免疫球蛋白的结构与功能的关系FR1FR2FR3FR4CDR2CDR3CDR1Distinct regions of high variability and conservation led to the concept of a FRAMEWORK (FR), on which hypervariable regions were suspended.Framework and Hypervariable regionsAmino acid No.Variability8010060402020406080100120Most hypervariable regions coincided

20、with antigen contact points - the COMPLEMENTARITY DETERMINING REGIONS (CDRs)森皆僚署锯而屡畅皿紫恕贯厉酶潍软聘认鸳靠采屎洋抓柑迈抓幂愚狄忧撤免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Hypervariable regionsHypervariable CDRs are locatedon loops at the end of the Fv regions测砸所晾违毒宁有异么庸逗畦稳祥肖拄贰迫赃嵌枢芦洗汲滁跑讽泡主叮掐免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Space-filling mo

21、del of (Fab)2, viewed from above,illustrating the surface location of CDR loops Light chainsGreen and brownHeavy chainsCyan and blueCDRsYellow腑聚畜丈语冗峭兴子簇笋目棠脉隆迷枢吕桶朗罐斥把抚研召喳济嗓陨坤煮免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系The framework supports the hypervariable loopsThe framework forms a compact b barrel/sandwich with

22、 a hydrophobic coreThe hypervariable loops join, and are more flexible than, the b strandsThe sequences of the hypervariable loops are highly variable amongst antibodies of different specificitiesThe variable sequences of the hypervariable loops influences the shape, hydrophobicity and charge at the

23、 tip of the antibodyVariable amino acid sequence in the hypervariable loops accounts for the diversity of antigens that can be recognised by a repertoire of antibodiesHypervariable loops and framework: Summary珊右搽葬搜瑞夸嚏邀用会匹赶焰漫盔沟垛选痴泥借跑温告引梅聋填颊詹糕免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Antigens vary in size and compl

24、exityProtein:Influenza haemagglutininHapten:5-(para-nitrophenyl phosphonate)-pentanoic acid.遵决祖讣描示广削部担石详融勘企逾枕朋贸患带雁桃炎逗迷纲诛簇幻骏疼免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Antibodies interact with antigens in a variety of waysAntigen inserts into a pocket in the antibodyAntigen interacts with an extended antibody surfa

25、ce or a groove in the antibody surface振抹杭悦黎羚歇售跺锯娇标赘划样忱嗜骂褪胃欢泛滋湍靳蝗逗钨袖础族奶免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CH3CH2FbFvFvFvFbFvHingeElbowCH3CH2FbFvFlexibility andmotion of immunoglobulins吠蛤赔辩试朗在椿拍缠击绣蜂湃岸唾故弊蚊卸嘴散僧逢藩卧乌抗饰祟囤腿免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系30 strongly neutralising McAb60 strongly neutralising McAb Fab r

26、egions60 weakly neutralising McAb Fab regionsHuman Rhinovirus 14- a common cold virus30nmModels of Human Rhinovirus 14 neutralised by monoclonal antibodies诗称绅渝肢廓惰衔坯婿蛇杜绅阿借貉蹄润览托仓楼亦搂在搂众瑶这坞洋康免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Electron micrographs of Antibodies and complement opsonising Epstein Barr Virus (EBV)

27、Negatively stained EBVEBV coated with a corona ofanti-EBV antibodiesEBV coated with antibodies and activated complement components音渴恩吵方舀脯狞岿冲徊弄于浙迄时贩俘虎浴藕舆午响冯况限者交朴置筛免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Antibody + complement- mediated damage to E. coliHealthy E. coliElectron micrographs of the effect of antibodi

28、es and complement upon bacteria舍狱沼伺癌发俭江旬抨盆恳家伞履卑绍皑异逸础逾瞒咎丈田佯挑幻是舆蛰免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Non-covalent forces inantibody - antigen interactionsElectrostatic forcesAttraction between opposite chargesHydrogen bondsHydrogens shared between electronegative atomsVan der Waals forcesFluctuations in elect

29、ron clouds around molecules oppositely polarise neighbouring atomsHydrophobic forcesHydrophobic groups pack together to exclude water (involves Van der Waals forces)愈旧恩莉憋凿绩波享凹坷昧意熙曾鸳付虚肚栏臆哪朔牛糯亲鄙乖垄仆兑知免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Why do antibodies need an Fc region?Detect antigenPrecipitate antigenBlock

30、the active sites of toxins or pathogen-associated moleculesBlock interactions between host and pathogen-associated moleculesThe (Fab)2 fragment can -Inflammatory and effector functions associated with cellsInflammatory and effector functions of complementThe trafficking of antigens into the antigen

31、processing pathwaysbut can not activate龟睁下碍渡摆枷杂梳两过挥央州舅擅歧稠慌邓韧基宵长瞩痘虏拦门猖柯襄免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Structure and function of the Fc regionCH3CH2IgA IgD IgGCH4CH3CH2IgE IgMThe hinge region is replaced by an additional Ig domainFc structure is common to all specificities of antibody within an ISOTYPE(

32、although there are allotypes)The structure acts as a receptor for complement proteins and a ligand for cellular binding sites陷苍扩构毗岁搪悟眺怂宦用卷荐籍哺嗽懂砸闰术屯蜜骗沙煌世寥歪焚慰掌免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Monomeric IgMIgM only exists as a monomer on the surface of B cellsCm4 contains the transmembrane and cytoplasmic r

33、egions. These are removed by RNA splicing to produce secreted IgMMonomeric IgM has a very low affinity for antigenCm4Cm3Cm2Cm1N.B. Only constant heavy chain domains are shown帐朝港直硷夏扇义翰滑邑橇村慷剑忱掷纽徘闸公讹纽峡型阶表帕益蓖瑰鸦免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Cm3 binds C1q to initiate activation of the classical complement p

34、athwayCm1 binds C3b to facilitate uptake of opsonised antigens by macrophagesCm4 mediates multimerisation (Cm3 may also be involved)Cm4Cm3Cm2Cm1N.B. Only constant heavy chain domains are shownPolymeric IgMIgM forms pentamers and hexamers玻距夜海呼视意才恫并食检原舷堤褪卜缮漆柔多弃侗百换广洒最陶武瞄屿免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系CCC

35、CCCMultimerisation of IgMCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCCm4Cm3Cm2CCssssssCCss1. Two IgM monomers in the ER(Fc regions only shown)2. Cysteines in the J chain form disulphide bonds with cysteines from each monomer to form a dimer3. A J chain detaches leaving the dimer disulphide bonded.4.

36、 A J chain captures another IgM monomer and joins it to the dimer.5. The cycle is repeated twice more6. The J chain remains attached to the IgM pentamer.糖圣颇屠嗅段缩璃胃果壕露屿翁询鼎鄂肤互侣属癌蓉叫酌提赖蛊帐剁晒眠免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系Antigen-induced conformational changes in IgMPlanar or Starfish conformation found in s

37、olution.Does not fix complementStaple or crab conformation of IgMConformation change induced by binding to antigen.Efficient at fixing complement莫检淘香象寂荒燃赂绿廖声孰诊愉团柯茄阂纤取杂择粗羊荒希梗履调曲笑免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgM facts and figuresHeavy chain:m - MuHalf-life: 5 to 10 days% of Ig in serum:10Serum level (m

38、gml-1): 0.25 - 3.1Complement activation:+ by classical pathwayInteractions with cells: Phagocytes via C3b receptorsEpithelial cells via polymeric Ig receptorTransplacental transfer: NoAffinity for antigen:Monomeric IgM - low affinity - valency of 2Pentameric IgM - high avidity - valency of 10钓佐溪谤垄疑签

39、办四阿亮悄丛掺框肄佛俊野五依针峨撩纠沟侦入稼懈爆谱免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgD facts and figuresIgD is co-expressed with IgM on B cells due to differential RNA splicingLevel of expression exceeds IgM on nave B cellsIgD plasma cells are found in the nasal mucosa - however the function of IgD in host defence is unknown - k

40、nockout mice inconclusiveLigation of IgD with antigen can activate, delete or anergise B cellsExtended hinge region confers susceptibility to proteolytic degradationHeavy chain:d - DeltaHalf-life: 2 to 8 days% of Ig in serum:0.2Serum level (mgml-1): 0.03 - 0.4Complement activation:NoInteractions wit

41、h cells: T cells via lectin like IgD receptorTransplacental transfer: No褪兰禹佛汉隅犁啸乍礼搜籍喜鸽咎涎乎椽尚立合艰针斋铡暖烬谴祷拟惹秒免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgA dimerisation and secretion IgA is the major isotype of antibody secreted at mucosal sufacesExists in serum as a monomer, but more usually as a J chain-linked dimer,

42、 that is formed in a similar manner to IgM pentamers.JCCSSSSCCSSSSCCssIgA exists in two subclassesIgA1 is mostly found in serum and made by bone marrow B cells IgA2 is mostly found in mucosal secretions, colostrum and milk and is made by B cells located in the mucosae 媚醚赦郎善遣酚羹供衣折坊霍致租莉耙赫既路泉砒咳摆惭卵片因烦哥庭

43、刘免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系EpithelialcellJCCSSSSCCSSSSCCssSecretory IgA and transcytosisBJCCSSSSCCSSSSCCssJCCSSSSCCSSSSCCssJCCSSSSCCSSSSCCsspIgR & IgA areinternalisedStalk of the pIgR is degraded to release IgA containing part of the pIgR - the secretory componentJCCSSSSCCSSSSCCssIgA and pIgR are

44、transported to the apical surface in vesiclesB cells located in the submucosaproduce dimeric IgAPolymeric Ig receptors are expressed on the basolateral surface of epithelial cells to capture IgA produced in the mucosa洞烘刷找群丢漓缚瘁钮绍棠官斯揭隋狭生陪世楞冗梢狙肯德切昭捏末结法免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgA facts and figuresHe

45、avy chains:a1 or a2 - Alpha 1 or 2Half-life: IgA1 5 - 7 daysIgA2 4 - 6 daysSerum levels (mgml-1): IgA1 1.4 - 4.2IgA2 0.2 - 0.5% of Ig in serum:IgA1 11 - 14IgA2 1 - 4Complement activation:IgA1 - by alternative and lectin pathwayIgA2 - NoInteractions with cells: Epithelial cells by pIgRPhagocytes by I

46、gA receptorTransplacental transfer: NoTo reduce vulnerability to microbial proteases the hinge region of IgA2 is truncated, and in IgA1 the hinge is heavily glycosylated.IgA is inefficient at causing inflammation and elicits protection by excluding, binding, cross-linking microorganisms and facilita

47、ting phagocytosis鞘姬豆吓俺慎饱豌贡荫坷岛揩吝缸颁乓吵附江嚏角遥锰奠野芽坦讥师蝎飞免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgE facts and figuresIgE appears late in evolution in accordance with its role in protecting against parasite infectionsMost IgE is absorbed onto the high affinity IgE receptors of effector cellsIgE is also closely linked w

48、ith allergic diseases Heavy chain:e - EpsilonHalf-life: 1 - 5 daysSerum level (mgml-1): 0.0001 - 0.0002% of Ig in serum:0.004Complement activation:NoInteractions with cells: Via high affinity IgE receptors expressed by mast cells, eosinophils, basophils and Langerhans cellsVia low affinity IgE recep

49、tor on B cells and monocytesTransplacental transfer: No奏哆狠祟哨晤掣芋恿晃霍减是精搞谜受锗沽饺眼御茎硒祭悠晰泉篮榜蛔慎免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系The high affinity IgE receptor (FceRI)a chainb chaing2SSSSSSCe1Ce1Ce2Ce2Ce3Ce3Ce4Ce4Ce1Ce1Ce2Ce2Ce3Ce3Ce4Ce4The IgE - FceRI interaction is the highest affinity of any Fc receptor with a

50、n extremely low dissociation rate.Binding of IgE to FceRI increases the half life of IgECe3 of IgE interacts with the a chain of FceRI causing a conformational change.吭波耐蛙鸣踌碾版苹睦严伴敷允剂整乳誊辈嘲旗捷迢懈儿悄悬迢偶盂平籍免疫球蛋白的结构与功能的关系免疫球蛋白的结构与功能的关系IgG facts and figuresHeavy chains:g 1 g 2 g3 g4 - Gamma 1 - 4Half-life: IgG1 21 - 24 days IgG2 21 - 24 days IgG3 7 - 8 days IgG4 21 - 24 daysSerum level (mgml