Physicl Biochemistry CHEM 728
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This 34 page Class Notes was uploaded by Dr. Drew Flatley on Friday October 30, 2015. The Class Notes belongs to CHEM 728 at University of Massachusetts taught by Craig Martin in Fall. Since its upload, it has received 17 views. For similar materials see /class/232347/chem-728-university-of-massachusetts in Chemistry at University of Massachusetts.
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Date Created: 10/30/15
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 Transcriptional control enhancer gene promoter Translational control Protein quantity concentration Regulation of Protein Function repressor ene Transcriptional control enhancer g promoter Translational control Protein quantity concentration AAA AA 5 Cap EMAA 5 Cap AAAA Regulation of Protein Function repressor ene Transcriptional control enhancer g promoter Translational control Protein quantity concentration AAA AA 5 EMAA p 5 cap AAAA Regulation of Protein liunction LysNHz Protein lifetime Intrinsic stability Tagged for destruction polyUbiquitination Targeted to proteasome Cleaved to short polypeptides I IN Regulation of Protein Function Ubiquitination multienzyme pathway mm ubiquitin ligase adds to a near Nterm Lys How targeted phosphorylation hydroxylation Nterm aa identity Protective Met Ser Thr Ala Val Cys Gly Pro Why I 39 Quality temporal control Regulation of Protein Function Spacial targetingco Iocalization Regulation of Protein Function h a msmnnns Dlasm inlnlmu im mamm Transcriptional control Tranglatlonal control Protein quantity concentration Protein lifetime Spacial targetingcoIocalization Binding of effector molecules nonoovalent modification Covalent modification pl l and redox environment Regulation of Protein Function h Spaoial targetingoolooalization More common in eukaryotes as there are more compartments in an organelle attached to a membrane attached to cytoskeleton associated with above May allow eukaryotes to do more with lessquot le Achievedsignaled by iiucieareiwempe localization sequences posttranslational modification Binding to scaffold membrane WSW Regulation of Protein Function Localization signals sequences h quotWWW Endoplasmic reticulum KDEL mfmmimffmm targets to ER and ultimately to plasma membrane Nuclear localization KRKR targets to nucleus Others extracellular secretion mitochondrial import lens Can be Nterminal Cterminal or even internal sequences in the protein in iiucleai euvelupe lysasmra Regulation of Protein Function 391 illnsma mzmnrane mums Posttranslational modification differ from intrinsic localization signals in that they regulatable Phosphorylation of Ser Tyr Thr by protein kinases oftused in signaling nucleus iiucleai Envelope nuclear PU n endqniasmm 39eliculuni h a manian Regulation of Protein Function lllnsm inmmenmic lilamcnls r i i mil yr 7 V U V L 7L Lilia 1 Binding to scaffold membrane WET an r nimnis 39R 7 I n 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 membrane lipids bind PH domain Mliunm39 quot quot nucleus iiucleai envelope Regulation of Protein Function Probably the most well recognized form of enzyme modulation inhibitor and activators metabolic sunstrate intermadtate 39 l i enzyme 1 enzyme 2 endrproduct bound to amive sue of enzyme 1 shuts down pathway n Probably the most well Binding of effector molecules recogn39zed form noncovalent modi cation enzyme mOdUIat39on inhibitor and activators ll metabolic p l suhslrale intermediate 0 39 I l 1 i enzyme 1 enzyme 2 endrproduct hound m am we sue of 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 suhslrale o 3 1 J oo o 1 0 I V V enzyme 1 emyme z endrproduct bound in active sxte or 16an 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 A a Binding at one site makes binding at mndingumgm Wow the second site stronger Eggnay i itwaanunalnmngein Negative cooperativity n Binding at one site makes binding at the second site weaker llSlS39Ql l ila i lgill iA Reflects flexibility in structure binding at 1 one site distorts the other 39 39 39 39 39 39 39 til it l l L2 CooperatIVIty is only present In oligomeric fnc ggmiuggnfeag ye c gseuimiu A proteins where there are 2 2 subunits each with a binding site forthe ligand 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 Regulation of Protein Function 0 Binding of effector molecules noncovalent modification 0 Allostery action at a distance Advertisement Chem 728 Al losteric 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 m an one site distorts the other x xl Cooperativity is only present in oligomeric proteins where there are 2 2 subunits 83 83 each with a binding site for the ligand m an Regulation of Protein Function 0 Allostery Effector ligand can be a small molecule or another protein Hemoglobin 02 o 02 binding to one subunit activates remaining subunits a l 3 3 gtlt O x gi lt33 quot Q 39 RH X I x 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 ATP R stale Regulation of Protein Function Allostery Effector ligand can be a small molecule or another protein i 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 sennewltn pnnspnaie A gig3 III fur Covalent modification Ph sph rylati n f 8939 H gt V induces movement of a loop 39 quot that priorto phosphorylation is blocking the active site Glycogen phosphorylase Regulation of Protein Function serine with phosphate VI vvvvl I VI IVUVI IVI IUUV Regulation of Protein Function Phosphorylation of SerTyr hydroxyl and HisAsp o protein kinases From onrein Slrunureand Funuton by Gregory A Persko and Dagmar nge Removed by protein phosphatases isocitrate Controlled reversibility M 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 Gproteins GTPases Conserved sequence motifs PIoop binds dBphosphate Local flexibility GX4GKST Switchl DXnT Switch GXzG Guanine basebinding region NTKXD Motor proteins ATPases PIoop GXAGKST Switch I NXzSSR Switch DXzG Adenine basebinding region p Regulation of Protein Function quota 125 7 pKa39 pKa42 H I mnllllll g o 1 kscoun V Lquotmon 0 V r 7 if f 9 l n gt mum mm M Aw kill 5391 say R E E S Nll y 0 6 1 s39 39 39 l f f x 00 x at mlannlnu Wslalna suamglna Glutamlnn K lelmlna W vng 8 3 39x n can ms pKz60 a xi 3 Amplilnallllv i fa ogf 5mm fQo sw 7 f mm mm W m quotwillquot in w M w pKa1o5 pKa101 pH and redox environment protonationdeprotonation changes local charge redox state change changes charge coordination redox change favorsdisfavors disulfide bond Regulation of Protein Function pH and redox environment protonationdeprotonation changes local charge cathepsin is activated in the endosome Nterminus binds in substrate binding site open substrate binding sute catalytic residues protonated neutral pH Regulation of Protein Function pH and redox environment protonationdeprotonation changes local charge redox state change changes charge looordination redox change favorsdisfavors disulfide bond my diptheria toxin A r o H 3 zRb 57 343 Y5 Y5 Y3 low pH amp reducing potential endosome oieesrzuul New Scimr Pvcss Regulation of Protein Function From Protein Structure and Funttiu by Gregory A Petsko and Dagmar Ringe intrinsic pathway k x iiifgf Proteolyttc cascade 39 extrinsic pathway trauma WW E o Covalent modification proteolysis I trypsinogen gt trypsin omit plasminogen gt plasmin I throinbm iibrinn en prothrombin gt thrombin I him it I I mm o magnum New Swim P39css Regulation of Protein Function re eased i39ltelr nlem helm sp iclng 43quot F C 639 xi No b N extein C extem Covalent modification splicing nomenclature similar to that of nucleic acids exonintron exteinintein Regulation of Protein Function SltH N M u Cextam 0 H o fl39gzii 773777quot XH 039 Ma 0 1 w HzN up Covalent modi cation spllcmg Kai H U HLN HX nomenclature Similar to that of D W nucleic acids H exonIntron extelnInteln 1 UAW 0 t d t 39 ATP A w one 5 ep so 065 no rrequIre MANk
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