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Sllde Ms lnvolvlng addlLlon lnclude acylaLlon of Lhe proLeln Lermlnus n group usually aL Lhe aceLyl Lhe addlLlon of an aceLylaLlon group eg meLhyl eLhyl alkyl f an Lhe addlLlon o alkylaLlon resldues hls ls a arglnlne or lyslne group usually aL meLhyl Lhe addlLlon of a meLhylaLlon Lype of alkylaLlon demeLhylaLlon Lermlnus aL C amldaLlon resldues wlLh a bloLln appendage lyslne acylaLlon of conserved bloLlnylaLlon formylaLlon vlLamln k dependenL on ylaLlon carbox gamma resldues Lo Lubulln and some oLher acld gluLamlc enL llnkage of coval gluLamylaLlon Lamylase polyglu Lubulln See proLelns or serlne hydroxylyslne asparaglne group Lo elLher glycosyl Lhe addlLlon of a glycosylaLlon whlch ls regarded as a glycaLlon ulsLlncL from glycoproLeln resulLlng ln a Lhreonlne nonenzymaLlc aLLachmenL of sugars C Lubulln resldues Lo Lhe glyclne covalenL llnkage of one Lo more Lhan glycylaLlon Lermlnal Lall moleLy may be covalenLly aLLached heme hydroxylaLlon Lhyrold hormones eg of lodlnaLlon group eg farnesol and geranylgeranlol lsoprenold Lhe addlLlon of an lsoprenylaLlon aLLachmenL of a llpoaLe funcLlonallLy llpoylaLlon prenylaLlon formaLlon Cl anchor myrlsLoylaLlon farnesylaLlon geranylgeranylaLlon or derlvaLlves Lhereof may be covalenLly aLLached nucleoLldes osylaLlon rlb Au aLLachmenL flavln oxldaLlon pegylaLlon may be covalenLly aLLached phosphaLldyllnoslLol coenzyme phosphopanLeLhelnyl moleLy from Lhe addlLlon of a phosphopanLeLhelnylaLlon rlbosomal pepLlde and leuclne blosynLhesls as ln faLLy acld polykeLlde non A or Lhreonlne Lyroslne serlne group usually Lo phosphaLe Lhe addlLlon of a phosphorylaLlon hlsLldlne formaLlon pyrogluLamaLe lsomerase prolyl by prollne of racemlzaLlon arglnylaLlon medlaLlon addlLlon of amlno aclds such as LnA Lyroslne Lhe addlLlon of a sulfaLe group Lo a sulfaLlon selenoproLelns ln selenlum LranslaLlonal lncorporaLlon of co SelenoylaLlon SulfaLlon Ms nvovng addton of other protens or peptdes SLlmulaLed Cene llnkage Lo Lhe lSC proLeln lnLerferon covalenL lSCylaLlon Lhe relaLed MCdlfler Small ublqulLln SuMC proLeln llnkage Lo Lhe covalenL Lhe SuMCylaLlon llnkage Lo Lhe proLeln ublqulLln covalenL Lhe ublqulLlnaLlon Ms nvovng changng the chemca nature of amno acds clLrulllne Lo arglnlne Lhe converslon of demnaton or clLrulllnaLlon asparLlc acld Lo asparaglne or acld gluLamlc Lo gluLamlne Lhe converslon of deamldaLlon Ms nvovng structura changes amlno aclds cysLelne Lhe covalenL llnkage of Lwo dlsulflde brldges cleavage of a proLeln aL a pepLlde bond cleavage proLeolyLlc ase exampes lnsulln cleavage and formaLlon of dlsulflde brldges durlng Lhe producLlon of nA polymerase conLrol by chromaLln as regulaLlon of LranscrlpLlon hlsLones M of sLrucLure nA polymerase ll M of nA polymerase ll as regulaLlon of LranscrlpLlon xterna Lnks ulfferenLlal M ueLecLlon afLer mass specLromeLry delLaMasses ranslaLlonal A CompuLaLlonal roLocol for ldenLlflcaLlon of osL Server AuLoMoLlf ModlflcaLlons ln roLeln Sequences of a LargeL proLeln ln cells phosphorylaLlon speclflc luncLlonal analyses for slLe Sllde renyaton renylaLlon refers Lo Lhe addlLlon of Lhe carbon farnesyl group or Lhe carbon geranylgeranyl group Lo accepLor proLelns boLh of whlch are lsoprenold compounds derlved he lsoprenold groups are aLLached Lo cysLelne synLheLlc paLhway cholesLerol blo from Lhe resldues aL Lhe carboxy Lermlnus of proLelns ln a LhloeLher llnkage CSC A common consensus sequence aL Lhe CLermlnus of prenylaLed proLelns has been ldenLlfled and ls composed of CAAx where C ls cysLelne A ls any allphaLlc amlno acld excepL alanlne and x ls Lhe CLermlnal amlno acld ln order for Lhe prenylaLlon reacLlon Lo occur Lhe Lhree C Lermlnal amlno aclds AAx are flrsL removed lollowlng aLLachmenL of Lhe prenyl group Lhe carboxylaLe of Lhe cysLelne ls meLhylaLed ln a reacLlon uLlllzlng SadenosylmeLhlonlne as Lhe meLhyl donor ln addlLlon Lo numerous prenylaLed proLelns LhaL conLaln Lhe CAAx consensus prenylaLlon ls known Lo occur on proLelns of Lhe A famlly of ASrelaLed CproLelns here are aL leasL proLelns ln Lhls famlly LhaL are prenylaLed aL elLher a CC or CxC elemenL ln Lhelr C Lermlnl he A famlly of proLelns are lnvolved ln slgnallng paLhways LhaL conLrol lnLracellular membrane Lrafflcklng Some of Lhe mosL lmporLanL proLelns whose funcLlons depend upon prenylaLlon are Lhose LhaL modulaLe lmmune responses hese lnclude proLelns lnvolved ln leukocyLe moLlllLy acLlvaLlon and prollferaLlon and endoLhellal cell lmmune funcLlons lL ls Lhese lmmune modulaLory roles of many prenylaLed proLelns LhaL are Lhe basls for a porLlon of Lhe anLl lnhlblLlng drugs due Lo a of cholesLerol synLhesls class sLaLln lnflammaLory acLlons of Lhe reducLlon ln Lhe synLhesls of farnesylpyrophosphaLe and geranylpyrophosphaLe and Lhus reduced exLenL of lnflammaLory evenLs CLher lmporLanL examples of prenylaLed proLelns lnclude Lhe oncogenlc Cblndlng and hydrolyzlng proLeln AS and Lhe subunlL of Lhe vlsual proLeln Lransducln boLh of whlch are farnesylaLed ln addlLlon numerous Cblndlng cascades have slgnal LransducLlon proLelns of and hydrolyzlng proLelns Lermed C subunlLs modlfled by geranylgeranylaLlon ependent Modfcatons Vtamn back Lo Lhe Lop as a cofacLor lnclude prollne and vlLamln C LhaL depend upon ModlflcaLlons of proLelns lyslne hydroxylaLlons and carboxy Lermlnal amldaLlon he hydroxylaLlng enzymes are ldenLlfled as prolyl hydroxylase and lysyl hydroxylase he donor of Lhe amlde for CLermlnal amldaLlon ls glyclne he mosL lmporLanL hydroxylaLed proLelns are Lhe collagens Several pepLlde hormones such as oxyLocln and vasopressln have CLermlnal amldaLlon ependent Modfcatons Vtamn k back Lo Lhe Lop ls a cofacLor ln Lhe carboxylaLlon of gluLamlc acld resldues he resulL of Lhls Lype vlLamln k of reacLlon ls Lhe formaLlon of a carboxygluLamaLe gammacarboxygluLamaLe referred Lo as a gla resldue tructure of a f resdue cascade ls crlLlcal blood cloLLlng he formaLlon of gla resldues wlLhln several proLelns of Lhe for Lhelr normal funcLlon he presence of gla resldues allows Lhe proLeln Lo chelaLe calclum lons and Lhereby render an alLered conformaLlon and blologlcal acLlvlLy Lo Lhe proLeln he coumarlnbased anLlcoagulanLs warfarln and dlcumarol funcLlon by lnhlblLlng Lhe carboxylaLlon reacLlon Sllde Mechanlsm of synLhesls of membrane bound or secreLed proLelns lbosomes engage Lhe L membrane Lhrough lnLeracLlon of Lhe slgnal recognlLlon parLlcle S ln Lhe rlbosome wlLh Lhe S recepLor ln Lhe L membrane As Lhe proLeln ls synLheslzed Lhe slgnal sequence ls passed Lhrough Lhe L membrane lnLo Lhe lumen of Lhe L AfLer sufflclenL synLhesls Lhe slgnal pepLlde ls removed by Lhe acLlon of slgnal pepLldase SynLhesls wlll conLlnue and lf Lhe proLeln ls secreLed lL wlll end up compleLely ln Lhe lumen of Lhe L lf Lhe proLeln ls membrane assoclaLed a sLop Lransfer moLlf ln Lhe proLeln wlll sLop Lhe Lransfer of Lhe proLeln Lhrough Lhe L membrane hls wlll become Lhe membrane spannlng domaln of Lhe proLeln Sllde However, recent evidence has shown that lysine methylation, similar to other covalent modiIications, can be transient and dynamically regulated by an opposing demethylation activity. Recent Iindings indicate that methylation oI lysine residues aIIects gene expression not only at the level oI chromatin, but also by modiIying transcription Iactors. Additional nitrogen methylations are Iound on the imidazole ring oI histidine, the guanidino moiety oI arginine and the Rgroup amides oI glutamate and aspartate. Methylation oI the oxygen oI the Rgroup carboxylates oI gutamate and aspartate also takes place and Iorms methyl esters. Proteins can also be methylated on the thiol Rgroup oI cysteine. As indicated below, many proteins are modiIied at their Cterminus by prenylation near a cysteine residue in the consensus CAAX. Following the prenylation reaction the protein is cleaved at the peptide bond oI the cysteine and the carboxylate residue is methylated by a prenylated protein methyltransIerase. One such protein that undergoes this type oI modiIication is the protooncogene RAS. Slide In lymphoid organs endothelial cells express oligs recognised by Lselectin on lymphocytes, causing them to loiter At inIlammation sites endothelial cells express selectins to catch white blood cells and platelets Collaboration with integrins Slide Some proteoglycans secreted as mucus, etc Slide Apical outside e.g. Iacing gut Tryp. uses phospholipases in plasma membrane Slide Most proteins undergo proteolytic cleavage Iollowing translation. The simplest Iorm oI this is the removal oI the initiation methionine. Many proteins are synthesized as inactive precursors that are activated under proper physiological conditions by limited proteolysis. Pancreatic enzymes and enzymes involved in clotting are examples oI the latter. Inactive precursor proteins that are activated by removal oI polypeptides are termed proproteins. A complex example oI posttranslational processing oI a preproprotein is the cleavage oI Peptide Hormones opiomelanocortin POMC synthesized in the pituitary see the prepro page Ior discussion oI POMC. This preproprotein undergoes complex cleavages, the pathway oI which diIIers depending upon the cellular location oI POMC synthesis. . Since insulin is secreted Irom the pancreas it insulin Another is example oI a preproprotein is has a prepeptide. Following cleavage oI the amino acid signal peptide the protein Iolds into proinsulin. Proinsulin is Iurther cleaved yielding active insulin which is composed oI two peptide chains linked togehter through disulIide bonds. Still other proteins oI the enzyme class are synthesized as inactive precursors called zymogens. Zymogens are activated by proteolytic cleavage such as is the situation Ior several cascade. blood clotting proteins oI the Slide Phosphorylation Posttranslational phosphorylation is one oI the most common protein modiIications that occurs in animal cells. The vast majority oI phosphorylations occur as a mechanism to regulate the biological activity oI a protein and as such are transient. In other words a phosphate or more than one in many cases is added and later removed. Physiologically relevant examples are the phosphorylations that occur in glycogen synthase and glycogen phosphorylase in hepatocytes in response to glucagon release Irom the pancreas. Phosphorylation oI synthase inhibits its activity, whereas, the activity oI phosphorylase is increased. These two events lead to increased hepatic glucose delivery to the blood. The enzymes that phosphorylate proteins are termed kinases and those that remove phosphates are termed phosphatases. Protein kinases catalyze reactions oI the Iollowing type ATP protein phosphoprotein ADP In animal cells serine, threonine and tyrosine are the amino acids subject to phosphorylation. The largest group oI kinases are those that phsophorylate either serines or threonines and as such are termed serine/threonine kinases. The ratio oI phosphorylation oI the three diIIerent amino acids is approximately // Ior serine/threonine/tyrosine. Although the level oI tyrosine phosphorylation is minor, the importance oI phosphorylation oI this amino acid is proIound. As an example, the activity oI numerous growth Iactor receptors is controlled by tyrosine phosphorylation. Slide gure Fi binds very tightly to GDP, a guanine nucleotide exchange Iactor see Because eIF B, is required to cause GDP release so that a new GTP molecule can , designated eIF is inhibited when it is . The reuse oI eIF A Figure can be reused bind and eIF phosphorylated the phosphorylated eIF binds to eIFB unusually tightly, inactivating eIF B. There is more eIF than eIFB in cells, and even a Iraction oI phosphorylated eIF can trap nearly all oI the eIFB. This prevents the reuse oI the nonphosphorylated eIF and . B Figure greatly slows protein synthesis Regulation oI the level oI active eIF is especially important in mammalian cells, being part oI the mechanism that allows them to enter a nonproliIerating, resting state called G in which the rate oI total protein synthesis is reduced to about oneIiIth the rate in proliIerating cells Slide The molecular switches Iall into two main classes that operate in diIIerent ways, although in both cases it is the gain or loss oI phosphate groups that determines whether the protein is active or inactive. The largest class consists oI proteins that are activated or inactivated by . For these proteins, the switch is thrown in one Chapter phosphorylation discussed in direction by a protein kinase, which adds one or more phosphate groups to the signaling protein, and in the other direction by a protein phosphatase, which removes the phosphate proteins in a third oI the . It is estimated that one A Figure groups Irom the protein eucaryotic cell are phosphorylated at any given time. The other main class oI molecular switches involved in signaling are Pbinding proteins . These switch between an active state when GTP is bound and an er Chapt discussed in inactive state when GDP is bound. Once activated, they have intrinsic GTPase activity and . There are two B Figure shut themselves oII by hydrolyzing their bound GTP to GDP major types oI GTPbinding proteins large trimeric GTPbinding proteins also called G , and B Figure ors see linked recept protein which relay the signals Irom G proteins, small monomeric GTPases also called monomeric GTPbinding proteins. The latter also help to relay intracellular signals, but in addition they are involved in regulating vesicular traIIic and many other processes in eucaryotic cells. Slide The mechanism is similar to the one just discussed that drives allosteric protein shape changes by GTP hydrolysis. Because a great deal oI Iree energy is released when ATP or GTP is hydrolyzed, it is very unlikely that the nucleotidebinding protein will undergo the reverse shape change needed Ior moving backward since this would require that it also reverse the ATP hydrolysis by adding a phosphate molecule to ADP to Iorm ATP Slide f fnfnf ff f ff nf f If ff nff fnfn f ff nf ff nfff f n nnf nfff fnffnf nf nfffn . ff f nfffn f f f ff ffff f ffnffnf f fnf f ff fff . nff nfffn f fffn f f ff nfffn ff ff fn fffn ffn f fff f fff fnf f ffffnnf ff f ffff fn fffnf f .f nffD. f nff .fD f.f f nff f D.nfnnffffn nf fnfn ff nffnfnfffffnfn .nfnf nffnffn nnff nfffff . ff nffff n . fffn fn nf n .nffn ..ffffn f f f.f f. . nfn nfff nnfffn f ffnf fnf fffnn nfn n nff fffnn fnf ff.ffnnf fff . . n nnf. ff f n. O. n fffnffnnfffO . fffn ffnnn. fffnOf ffn nf fnfffn ff fffnf. On f nnf f fff ffffff. . . 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