分子生物学双语.pptx
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1、Chapter 10ChromatinIndividual nucleosomes are released by digestion of chromatin with micrococcal nuclease.The bar is 100 nmReprinted from Cell,vol.4,P.Oudet,M.Gross-Bellard,and P.Chambon,Electron microscopic and biochemical evidence.,pp.281-300.Copyright 1975,with permission from Elsevier http:/ co
2、urtesy of Pierre Chambon,College of France.10 nm fiber A linear array of nucleosomes generated by unfolding from the natural condition of chromatin.linker histones A family of histones(such as histone H1)that are not components of the nucleosome core.Linker histones bind nucleosomes and/or linker DN
3、A and promote 30 nm fiber formation.Basic Structures The 10 nm fiber in partially unwound state can be seen to consist of a string of nucleosomesPhoto courtesy of Barbara Hamkalo,University of California,Irvine.The 10 nm fiber is a continuous string of nucleosomes30 nm fiber A coil of nucleosomes.It
4、 is the basic level of organization of nucleosomes in chromatin.nonhistone Any structural protein found in a chromosome except one of the histones.Basic Structures The 30 nm fiber has a coiled structurePhoto courtesy of Barbara Hamkalo,University of California,Irvine.DNA Is Organized in Arrays of Nu
5、cleosomes MNase(micrococcal nuclease)cleaves linker DNA and releases individual nucleosomes from chromatin.95%of the DNA is recovered in nucleosomes or multimers when MNase cleaves DNA in chromatin.The length of DNA per nucleosome varies for individual tissues or species in a range from 154 to 260 b
6、p.Nucleosomal DNA is divided into the core DNA and linker DNA depending on its susceptibility to MNase.Micrococcal nuclease digests chromatin in nuclei into a multimeric series of DNA bands that can be separated by gel electrophoresis.Each multimer of nucleosomes contains the appropriate number of u
7、nit lengths of DNAPhoto courtesy of Markus Noll,Universitt Zrich.Footprinting:Characterizing RNA PolymerasePromoter and DNAProtein Interactions footprinting A technique for identifying the site on DNA bound by some protein by virtue of the protection of bonds in this region against attack by nucleas
8、es.A protein protects a series of bonds against nuclease attackFIGURE 05:Micrococcal nuclease initially cleaves between nucleosomesThe nucleosome is a cylinder with DNA organized into 1 2/3 turns around the surfaceDNA occupies most of the outer surface of the nucleosomeSequences on the DNA that lie
9、on different turns around the nucleosome may be close togetherThe nucleosome consists of approximately equal masses of DNA and histones(including H1)Possible model for the interaction of histone H1 with the nucleosome202122 The Nucleosome Is the Subunit of All ChromatinEach histone is extensively in
10、terdigitated with its partner.All core histones have the structural motif of the histone fold.N-and C-terminal histone tails extend out of the nucleosome.H1 is associated with linker DNA and may lie at the point where DNA enters or exits the nucleosome.Photos courtesy of E.N.Moudrianakis,Johns Hopki
11、ns University.FIGURE 10ab:The crystal structure of the histone core octamer is represented in a space-filling model25Linker DNA is the region of 8 to 114 bp,and this is the region that is susceptible to early cleavage by the enzyme.Changes in the length of linker DNA account for the variation in tot
12、al length of nucleosomal DNA.H1 is associated with linker DNA and may lie at the point where DNA enters and leaves the nucleosome.The histone fold consists of two short a-helices flanking a longer a-helixStructures from Protein Data Bank 1HIO.G.Arents,et al.,Proc.Natl.Acad.Sci.USA 88(1991):10145-101
13、52.Histone pairs(H3+H4 and H2A+H2B)interact to form histone dimersStructures from Protein Data Bank 1HIO.G.Arents,et al.,Proc.Natl.Acad.Sci.USA 88(1991):10145-10152.The crystal structure of the histone core octamer is represented in a ribbon modelStructures from Protein Data Bank 1AOI.K.Luger,et al.
14、,Nature 389(1997):251-260.The crystal structure of the histone core octamer is represented in a ribbon modelStructures from Protein Data Bank 1AOI.Luger,K.,et al.,Nature 389(1997):251-260.FIGURE CO:ChromatinStructure from Protein Data Base 1ZBB.T.Schalch,et al.,Nature 436(2005):138-141.Photo courtes
15、y of Chris Nelson,University of Victoria.The 30 nm fiber is a two start helix consisting of two rows of nucleosomes coiled into a solenoidReprinted from Cell,vol.128,D.J.Tremethick,Higher-order structure of chromatin.,pp.651-654.Copyright 2007,with permission from Elsevier http:/ histone tails are d
16、isordered and exit from both faces of the nucleosome and between turns of the DNAStructure from Protein Data Bank 1AOI.K.Luger,et al.,Nature 389(1997):251-260.FIGURE 13:The histone fold domains of the histones are located in the core of the nucleosome37Figure 29.20:The structures of histone tails ar
17、e not defined.Figure 29.21:Histone tails emerge between DNA turns.38Histone tails have many sites of modificationAdapted from The Scientist 17(2003):p.27.The positive charge on lysine is neutralized upon acetylation,while methylated lysine and arginine retain their positive charges41FIGURE 20:Most m
18、odified sites in histones have a single,specific type of modification,but some sites can have more than one type of modification43FIGURE 18:Acetylation during replication occurs on specific sites on histones before they are incorporated into nucleosomesFIGURE 19:Acetylation associated with gene acti
19、vation occurs by directly modifying specific sites on histones that are already incorporated into nucleosomes46Figure 2.Proposed mechanism by which DNA methylation leads to transcriptional repression.(a)Transcriptionally active chromatin is predominantly unmethylated and has high levels of acetylate
20、d histone tails(short black squiggles).(b)Methylation at CpG dinucleotides can be carried out by one of the three known human DNA methyltransferases(DNMT1,3a and 3b),resulting in DNA with high levels of CpG methylation(purple circles),but still containing predominantly acetylated histone tails.DNA i
21、n this form would still be expected to be transcriptionally competent.(c)Methylated DNA is targeted by methyl-binding domain(MBD)proteins such as MBD2 and MeCP2,which are found associated with large protein complexes such as the NuRD complex(MBD2)and the Sin3a complex(MeCP2).Histone deacetylase(HDAC
22、1 and 2)and chromatin-remodelling activities(Mi-2 and Sin3a)within these complexes result in alterations in chromatin structure,producing chromatin that is refractory to transcriptional activation(pink streaks represent deacetylated histone tails).The functional roles of other components in these co
23、mplexes are not yet known.Abbreviations:MTA2,metastasis-associated protein 2;RbAp46/48,retinoblastoma-associated protein 46/48;RNA pol II,RNA polymerase II;SAP18/30,Sin3-associated polypeptides 18/30(fig002gsb).Proposed mechanism by which DNA methylation leads to transcriptional repressionG.Strathde
24、e and R.Brown47 Covalent Modification of HistonesPhoto courtesy of Sean D.Taverna,Johns Hopkins University School of Medicine,and Haitao Li,Memorial Sloan-Kettering Cancer Center.Additional information at S.D.Taverna,et al.,Nat.Struct.Mol.Biol.14(2007):1025-1040.Numerous protein motifs recognize met
25、hylated lysinesBromodomains are protein motifs that bind acetyl lysinesStructure from Protein Data Bank 1E6I.D.J.Owen,et al.,EMBO J.19(2000):6141-6149.Numerous protein motifs recognize methylated lysinesStructure from Protein Data Bank 1KNE.S.A.Jacobs and S.Khorasanizadeh,Science 295(2002):2080-2083
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