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Structure of the DNA-binding motifs of activators Chapter 12 Categories of Activators • Activators can stimulate or inhibit transcription by RNA polymerase II • Structure is composed of at least 2 functional domains – DNA-binding domain – Transcription-activation domain – Many also have a dimerization domain DNA-binding domains • DNA-binding domains have DNA-binding motif – Part of the domain having characteristic shape specialized for specific DNA binding – Most DNA-binding motifs fall into 3 classes Zinc-containing modules • There are at least 3 kinds of zinc-containing modules that act as DNA-binding motifs • All use one or more zinc ions to create a shape to fit an α-helix of the motif into the DNA major groove – Zinc fingers – TFIIIA and Sp1 – Zinc modules – Glucocorticoid receptor – Modules containing 2 zinc and 6 cysteines – GAL4 Homeodomains • These domains contain about 60 amino acids • Resemble the helix-turn-helix proteins in structure and function • Found in a variety of activators • Originally identified in homeobox proteins regulating fruit fly development bZIP and bHLH Motifs • A number of transcription factors have a highly basic DNA-binding motif linked to protein dimerization motifs – Leucine zippers – Helix-loop-helix • Examples include: – CCAAT/enhancer-binding protein – MyoD protein Transcription-Activation Domains • Acidic domains: GAL4 • Glutamine-rich domains: Sp1 • Proline-rich domains: CTF • Structure and function – not clearly related The GAL4 Protein • Yeast activator controls a set of genes responsible for metabolism of galactose • The GAL4 protein is a member of the zinccontaining family of DNA-binding proteins Nuclear receptor • Zinc module - nuclear receptor • This type of protein interacts with a variety of endocrine-signaling molecules • Protein plus endocrine molecule forms a complex that functions as an activator by binding to hormone response elements and stimulating transcription of associated genes Type I Nuclear Receptors • These receptors reside in the cytoplasm bound to another protein • When receptors bind to their hormone ligands: – Release their cytoplasmic protein partners – Move to nucleus – Bind to enhancers – Act as activators Types II and III Nuclear Receptors • Type II nuclear receptors stay within the nucleus - Bound to target DNA sites - Without ligands the receptors repress gene activity - Bind ligands - they activate transcription • Type III receptors - ligands are not yet identified Functions of Activators • Bacterial core RNA polymerase is incapable of initiating meaningful transcription • RNA polymerase holoenzyme can catalyze basal level transcription – Often insufficient at weak promoters – Cells have activators to boost basal transcription to higher level in a process called recruitment Eukaryotic Activators • Eukaryotic activators also recruit RNA polymerase to promoters • Stimulate binding of general transcription factors and RNA polymerase to a promoter • 2 hypotheses for recruitment: – General TF cause a stepwise build-up of preinitiation complex – General TF and other proteins are already bound to polymerase in a complex called RNA polymerase holoenzyme Models for Recruitment Interaction Among Activators • General transcription factors must interact to form the preinitiation complex • Activators and general transcription factors also interact • Activators usually interact with one another in activating a gene – Individual factors interact to form a protein dimer facilitating binding to a single DNA target site – Specific factors bound to different DNA target sites can collaborate in activating a gene Action at a Distance • Bacterial and eukaryotic enhancers stimulate transcription even though located some distance from their promoters • Four hypotheses attempt to explain the ability of enhancers to act at a distance (homework) – – – – Change in topology Sliding Looping Facilitated tracking Hypotheses of Enhancer Action Complex Enhancers • Many genes can have more than one activatorbinding site permitting them to respond to multiple stimuli • Each of the activators that bind at these sites must be able to interact with the preinitiation complex assembling at the promoter - by looping out any intervening DNA Control Region of the Metallothionine Gene • Gene product helps eukaryotes cope with heavy metal poisoning • Turned on by several different agents Architectural Transcription Factors Architectural transcription factors are those transcription factors - change the shape control region so that other proteins can interact successfully to stimulate transcription Enhanceosome • An enhanceosome is a complex of enhancer DNA with activators contacting this DNA • An example is the HMG that helps to bend DNA so that it may interact with other proteins Examples of Architectural Transcription Factors • Besides LEF-1, HMG I(Y) plays a similar role in the human interferon-b control gene • For the IFN-b enhancer, activation seems to require cooperative binding of several activators, including HMG I(Y) to form an enhanceosome with a specific shape Homework • Explain the four hypotheses of the ability of enhancers to act at a distance. • What are insulators? Explain the functions of insulators. Explain mechanism of insulator activity. Study material for exam • • • • • • • • Structure of activator Three types of DNA binding motif Three types of transcription activation domain What is enhancer? Two types – architectural factors and enhanceosome Recruitment Insulator Ubiquitylation Sumoylation Regulation of Transcription Factors • Phosphorylation of activators can allow them to interact with coactivators that in turn stimulate transcription • Ubiquitylation of transcription factors can mark them for – Destruction by proteolysis – Stimulation of activity • Sumoylation is the attachment of the polypeptide SUMO which can target for incorporation into compartments of the nucleus • Methylation and acetylation can modulate activity Ubiquitylation • Ubiquitylation - monoubiquitylation of some activators can have an activating effect • Polyubiquitylation marks these same proteins for destruction Activator Sumoylation • Sumoylation is the addition of one or more copies of the 101-amino acid polypeptide SUMO (Small Ubiquitin-Related Modifier) to lysine residues on a protein • Process is similar to ubiquitylation • Results quite different – sumoylated activators are targeted to a specific nuclear compartment that keeps them stable Activator Acetylation • Nonhistone activators and repressors can be acetylated by HATs • HAT is the enzyme histone acetyltransferase which can act on nonhistone activators and repressors • Such acetylation can have either positive or negative effects • • • This project is funded by a grant awarded under the President’s Community Based Job Training Grant as implemented by the U.S. Department of Labor’s Employment and Training Administration (CB-15-162-06-60). 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