Class Note for CHEM 728 at UMass(1)
Class Note for CHEM 728 at UMass(1)
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This 28 page Class Notes was uploaded by an elite notetaker on Friday February 6, 2015. The Class Notes belongs to a course at University of Massachusetts taught by a professor in Fall. Since its upload, it has received 20 views.
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Date Created: 02/06/15
Regulation of Protein Function It s What makes the cell Regulation of Protein Function It s What makes the cell Transcriptional control Translational control Protein quantity concentration Protein lifetime Spacial targetingcolocalization Binding of effector molecules noncovalent modification Covalent modification pH and redox environment Regulation of Protein Function repressor gene enhancer promoter Transcriptional control Translational control Protein quantity concentration Regulation of Protein Function repressor gene Transcriptional control enhanceD promoter Translational control Protein quantity concentration AA 5 cap E AAAA 5 cap AAAA 5 cap AAAA Regulation of Protein Function repressor gene Transcriptional control enhanceD promoter Translational control Protein quantity concentration AA 5 cap AAAA 5 cap AAAA 5 cap AAAA i 1 Regulation of Protein Emunction i v substrate LysNHz Fl 39 I fl39i Y Protein lifetime Intrinsic stability Tagged for destruction U polyUbiquitination Targeted to proteasome Cleaved to short polypeptides Regulation of Protein Emunction I v subsuate ntnnsm Ubiquitination Egggggam multienzyme pathway W2 ubiquitin ligase adds to a near Nterm Lys HOW targeted WWW 1 phosphorylation hydroxylation V WWW Nterm aa identity Protective Met Ser Thr Ala Val Cys Gly Pro Why I quot Quality temporal control Regulation of Protein Function Spacial targetingco Iocalization Regulation of Protein Function meisnmu Localization signals sequences b Wmmm Endoplasmic reticulum KDEL tumuuu E targets to ER niierubulz 4 and ultimately to plasma membrane quot 5 I Nuclear localization KRKR targets to nucleus Others extracellular secretion mitochondrial import nucleus Can be Nterminal Cterminal or even internal sequences in the protein nucleai dinamps mirlenr pm ndvnlasmm 39ellcullmi mlmcnnn nan vzsiclz uuusam lysasmrz Regulation of Protein Function l lum Posttranslational modification differ from intrinsic localization signals in that they regulatable Phosphorylation of Ser Tyr Thr by protein kinases oftused in signaling nucleus nucleal Ellialum nuclear Pure ndqvlasmm 39ellcullml nllmcllnnnrlml vzslclz llbus lllE lysasmvz Regulation of Protein Function l Mm inlnrme ialc lilamcms m Binding to scaffold membrane WEST gt r m an r nimms Lipid anchoring covalently attach NICterminus to a lipid localizes soluble protein near membrane membrane structure can further localize such a protein Scaffold typically has a recognition domain SH3 domain binds Prorich seqs SH2 domain binds phosphorylated Tyr nimiemm membrane lipids bind PH domain Wm39wwiw lysasmva Regulation of Protein Function Probably the most well recognized form of enzyme modulation inhibitor and activators metabolic substrate Intermediate 0 39 C I enzyme 1 enzyme 2 endrprodttct name to active sue or enzyme 1 shuts down pathway Regulation of Protein Function Probably the most well recognized form of enzyme modulation inhibitor and activators Binding of effector molecules noncovalent modi cation metabolic substrate Intermediate 0 l T1 IWVVi endrproduct mm m acme snte or enzyme 1 shuts down pathway Regulation of Protein Function Binding of effector molecules noncovalent modification Competitive binding binds at active site displacing substrate or other effector molecule Noncompetitive binding allostery action at a distance eg effects kcat Common Feedback inhibition mm suhslrale Intermediate 0 C 1 o l o I 339 V I enzyme 1 enIyme 2 J endrproduct bound in active SttE ol enzyme l Sl lUlS own pathway Regulation of Protein Function Binding of effector molecules noncovalent modification Cooperativity between binding sites for the same ligand in which binding at one site affects affinity at the other Positive cooperativity Binding at one site makes binding at the second site stronger Negative cooperativity Binding at one site makes binding at the second site weaker Reflects flexibility in structure binding at one site distorts the other Cooperativity is only present in oligomeric proteins where there are 2 2 subunits each with a binding site forthe ligand 3 binding ur ligand L1 causes a Cunfulmatlullal change in subunit 9 i i cunruimaiiunal change in B altars binding site an subunit A sacund ligand mnlecula L2 aims mare readily to subunit A Regulation of Protein Function 0 Binding of effector molecules noncovalent modification 0 Allostery action at a distance Allosteric activator Binding at one site makes binding at the second site stronger Allosteric inhibitor Binding at one site makes binding at the second site weaker Reflects flexibility in structure binding at one site distorts the other Cooperativity is only present in oligomeric proteins where there are 2 2 subunits each with a binding site for the ligand X XI Regulation of Protein Function Allostery Effector ligand can be a small molecule or another protein Aspartate transcarbomylase ATP binding triggers change that opens active site for substrate binding Regulation of Protein Function Allostery Effector ligand can be a small molecule or another protein Dth repressor Binding of Fe2 alters spacing of major groove reading heads to allow proper fit in two consecutive major grooves Regulation of Protein Function sennewitn r pnnspnale Covalent modification Ph sph rylati n fser14 induces movement of a loop l Cl39lif W39ili that priorto phosphorylation is blocking the active site Glycogen phosphorylase VI vvaI I VI IVUVI IVI J IUUV serine with phosphate Regulation of Protein Function Regulation of Protein Function Phosphorylation of SerTyr hydroxyl and HisAsp 0 Added by protein kinases From Pvmein surname and Function by Gregory A Petsko and Dagmar nga Removed by protein phosphatases a isocitrate Controlled reversibility Adds a double negative charge to a polar but uncharged amino acid Adds electrostatic repulstion attraction Adds new Hbonding potential Adds potential recognition site for binding ofa second protein eg SH2 domains bind PTyr lsocitrate dehydrogenase phosphorylation of Ser 113 adds charge to substrate binding site Regulation of Protein Function Binding of effector molecules noncovalent modification Covalent modification Regulation of Protein Function Protein switches based on nucleotide hydrolysis From Protein Structure and Function Gproteins by Gregory A Petsko and Dagmar Ringe GTP bound presents a I Yphosphate GDP bound removes the Yphosphate GTP hydrolysis switches from first state to second Different proteins bind to the two states Motor proteins Same idea but with ATP Regulation of Protein Function GproteinsGTPases Conserved sequence motifs PIoop binds dBphosphate Local flexibility GX4GKST Switch DXnT 0 Switch GXzG Guanine basebinding region NTKXD Motor proteins ATPases PIoop GXAGKST Switch I NXzSSR Switch DXzG Adenine basebinding region RXRP Regulation of Protein Function pH and redox environment protonationdeprotonation changes local charge redox state change changes charge looordination redox change favorsdisfavors disulfide bond From Pmtein Strunure and Function by Gregory A Petsko and Dagmar Rings diptheria toxin 9 393 H 515 5H 5H HBEIIKE gt active VECEIMUI w ca aly ic domain low pH amp reducing potential endosome oieesrzuul New emu Pvcsa Regulation of Protein Function Covalent modification proteolysis trypsinogen gt trypsin plasminogen gt plasmin prothrombin gt thrombin From Protein Structure and Functiun by Gregory A Petsko and Dagmar Ringe inliinsin pathway damaged ussue k x i ii fu Proteolytic cascade 0 39 i 39 axlrinsicpalhway l i o 71 n I wt mm m I tissue iaoiur O mmmmni o marzum New Science P39css Regulation of Protein Function released l llCll ntem lichen sp iclng 39 A dw39c vc 0quot 9 N extein C extem Covalent modification splicing nomenclature similar to that of nucleic acids exonintron exteinintein Regulation of Protein Function Covalent modi cation splicing nomenclature similar to that of nucleic acids exonintron exteinintein one step so does not require ATP H mm 0 X N M H 0mm 0 qu 0 M fNHZ 7 Sim p a I 0 M7 H G l l W0 HX x gt I HzN cN H Him l r 4 U HIN HX D MED tux NH U til DZ CNH
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