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Lecture 3

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BIOC 212
Jason Young

BIOC 212Winter 2011Lecture 3 glucocorticoid receptors belong to a family of steroid hormone receptors respond to hormones by activatingrepressing genes in an inflammatory reaction ligand binding domain recognizes hormones DNAbinding domain binds to GR promoter elements GRENterminal activation domain regulated transcription of genesTPR Domain CoChaperonesusually bind only Hsp90 are adaptors that connect chaperones to different protein complexeslocationsFKBP52Pplase steroid receptor chaperonesTom40mitochondrial importCHIPubiquitin ligaseGR LBDhydrophobic steroid is bound in the interior of the LBD ligandbinding domain necessary to maintain native state without corticosteroids LBD cant fold stably chaperones keep LBD partially folded so it can bind hormones other domains of GR remain foldedSequential Action of ChaperonesLBD is folded by a defined sequence of chaperonesHsp40Hsc70Hsc70Hsp90Hsp90FKBP52p23 without hormone GR continues to cycle through the system with hormone GR becomes a stable dimerHSFIis a transcription factor regulator of the heat shock response has DNAbinding transcription activation and trimerization domains inactive HSFI is a monomer active it is a trimer and recognizes HSE heat shock element promotersHeat Shock Responseheat shock followed by a recovery period triggers a typical response1 Translation is inhibited immediately and recovers approximately 1hr after HS2 Transcription of Hsp is upregulated for 612 hours other proteins are downregulated3 Approximately 24 hours later everything returns to normalRegulation of HSFinactive HSF1 monomer mimics unfolded proteinbound by chaperone Hsp90 after HS Hsp90 binds unfolded proteins and HSFI is free to trimerize and activate transcription phosphorylation of HSF1 further controls activation HSF1 is downregulated by binding of excess chaperones to the monomer formProtein Degradationubiquitinmediated protein degradation by proteasomes in the cytosolubiqutin is a small 8kDa protein covalently bonded to lysine sidechains of itself and proteins polyubiquitin chains target a protein for proteasome degradation but not ubiquitin itselfUbiquitation Enzymes E1ubiquitinal enzyme attaches Ub in a chemically reactive state on U2E2ubiquitin conjugating enzyme transfers Ub to substrateE3ubiquitin ligase provides substrate specificity of ubiquitination there are many E3 fewer E1 and E2they control degradation Ub Cterminus carboxyl group is covalently linked to lysine sidechains via an isopeptide bond substrate can have multiple ubiquitination sites many but not ALL lysine depends on accessibilityUbiquitin Linkagescan be linked to either itself or lysine 48 or 63 polyubiquitin chains K48 linkage target proten for proteasome degradation K63 linkages activate different signals polymonoubiquitinMonoubiquitinationhistone regulationMultiubiquitinationendocytosisPolyubiquitinationK48 linkage proteasomal degradationK63 linkage DNA repairProteasome Subunits Core 2 outer rings of 2 similar alpha subunits 2 inner rings of similar beta units beta subunits have protease activity on their inside surface a 19s cap attaches to the outer rings base with 6 AAAfamily ATPase subunitsprotein unfoldase has a lid with nonATPase subunits polyUb receptors Ub hydrolasesAAA familyATPdependent proteins with many functions the proteasome is large has a central 20s cyliner and 19s caps cylinder and caps26s proteasome 25MDa performs general degradation in cytosol nucleus ERProteasome Functionlid recognizes polyUb chain Ub hydrolases remove polyUb and pass it to base base units use ATPase activity to unfold substrate and feed it into the 20s core 3 proteolytic subunits inside the core cleave substrate into fragments at basicacidichydrophobic sites
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