index.html

MCB 200 Fall 2007

Advanced Biochemistry & Molecular Biology

Section III

Professor Thorner's office hours are 4-5 pm on Fridays in his office, 526 Barker Hall (if there are too many students to fit in his office, a sign will be posted on where he has moved).

Because of the growing use of color in journal articles, Prof. Thorner has chosen to post the papers online rather than assemble a reader with only black and white figures.

If you have questions about this website, please contact Prof. Thorner's assistant, Kathleen Parsons, at 642-3574 or by email to kparsons@berkeley.edu

Lecture

Date

Topics

Handouts

Tuesday 11/6 NO CLASS

21

Thursday 11/8
Nucleocytoplasmic trafficking. Nuclear pore structure. Nuclear protein import. Nuclear protein and RNA export. Regulation of nucleocytoplasmic transport. Coupling of mRNA export to transcription, splicing, and quality control mechanisms. Novel roles of karyopherins in control of mitosis and other aspects of cell regulation.
Required reading:
Tran EJ, Wente SR (2006) Dynamic nuclear pore complexes: life on the edge. Cell 125: 1041-1053.
Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (2007) Classical nuclear
localization signals: definition, function, and interaction with importin-alpha. J. Biol. Chem. 282: 5101-5105.
Cole CN, Scarcelli JJ (2006) Unravelling mRNA export. Nature Cell Biol. 8: 645-647.

Lecture Materials: Outline, Reference List, Study Questions

Presentation Powerpoint or PDF

Quantitative Question #1 Answer

Discussion Paper: Frey S, Görlich D (2007) A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell 130: 512-523. Supp. material.

A user name and password is required to access journal article pdfs and the class presentation (Powerpoint slides). You must also be logged in to a UCB server. The user name and password will be announced in Thursday's class.

22
Tuesday 11/13
Protein synthesis. Review of ribosome structure. rRNAs, tRNAs, and their modifications. Translation factors. The translation cycle. Regulation of translation. Nutrient sensing and Tor signaling. Cell size control.

Required reading:

Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433: 477-480.

Proud CG (2007) Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J. 403: 217-234.

Fraser CS, Doudna JA (2007) Structural and mechanistic insights into hepatitis C viral translation initiation. Nature Rev. Microbiol. 5: 29-38.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #2 Answer

Discussion Paper: LaRonde-LeBlanc N, Santhanam AN, et al. (2007) Structural basis for inhibition of translation by the tumor suppressor PDCD4. Mol. Cell Biol. 27: 147-156.

23

Thursday 11/15
Protein folding in vivo. Chaperones (major heat shock / stress proteins). DnaK(Hsp70)-DnaJ(Hsp40)-GrpE. Hsp90. Hsp104. Co-chaperones. Chaperonins (GroEL/Hsp60-GroE/Hsp10 and TRiC/CCT cages). Peptidylprolyl-cis,trans-isomerases (FKBPs, cyclophilins, Ess1/Dodo/Pin1). Introduction of disulfide bonds. Prions.

Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nature Rev. Mol. Cell Biol. 5: 781-791.

Richter K, Reinstein J, Buchner J (2007) A Grp on the Hsp90 mechanism. Mol. Cell 28: 177-179.

Horwich AL, Farr GW, Fenton WA (2006) GroEL-GroES-mediated protein folding. Chem. Rev. 106: 1917-1930.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #3 Answer

Discussion Paper for Friday: Vogel M, et al. (2006) Allosteric regulation of Hsp70 chaperones involves a conserved interdomain linker. J. Biol. Chem. 281: 38705-38711.

24

Tuesday 11/20

Protein turnover. Bacterial tmRNA and C-terminal tagging. Ubiquitinylation in eukaryotes. Proteosome structure. SUMO and other ubiquitin-like modifications of proteins. Zymogen and precursor processing. Intein excision and its applications.
Kerscher O, Felberbaum R, Hochstrasser M (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22: 159-180.
Harper JW, Schulman BA (2006) Structural complexity in ubiquitin recognition. Cell 124: 1133-1136.
Goldberg AL (2007) Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem. Soc. Trans. 35: 12-17.

Lecture Materials: Outline, Reference List, Study Questions
Presentation: Powerpoint or PDF
Quantitative Question #4 Answer
Discussion Paper: Schwartz, et al. (2007) The Ulp2 SUMO protease is required for cell division following termination of the DNA damage checkpoint. Mol. Cell Biol. 27: 6948-6961.

Thursday 11/22

THANKSGIVING HOLIDAY - No class on Thursday and no discussion section on Friday

25

Tuesday 11/27

Signal transduction biochemistry. Topology and classification of cell surface receptors. Scaffolds, adaptor proteins, and modular recognition domains. Roles of lipids and ions in cell signaling.

Hubbard SR, Miller WT (2007) Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol. 19: 117-123.

Pawson T (2007) Dynamic control of signaling by modular adaptor proteins. Curr. Opin. Cell Biol. 19: 112-116.

Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nature Rev. Mol. Cell. Biol. 7: 473-483.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #5 Answer

Discussion Papers: Cherezov V, et al. (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318: 1258-1265. Supp material.

Rosenbaum DM, et al. (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318: 1266-1273. Supp material.

26

Thursday 11/29

Structure and regulation of G proteins. Ras and related small GTPases. Translation elongation factor EF-Tu. Heterotrimeric G proteins. GEFs, GAPs & RGS proteins. Other classes of GTP-binding proteins.

Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J. Cell Sci. 118: 843-846.

Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129: 865-877.

Oldham WM, Hamm HE (2006) Structural basis of function in heterotrimeric G proteins. Quart. Rev. Biophys. 39: 117-166.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #6 Answer

Discussion Paper: Ballon DR, et al. (2006) DEP-domain-mediated regulation of GPCR signaling responses. Cell 126: 1079-1093. Supp. material.

27

Tuesday 12/4

Bacterial two-component signaling systems. Prokaryotic protein kinases. Eukaryotic protein kinases. Phosphotransferase reaction mechanisms. Structural basis of phospho-acceptor (Ser/Thr, Tyr, and dual) specificity. Non-canonical protein kinases (ATM/ATR, DNA-PKcs, others).
Johnson SA, Hunter T (2005) Kinomics: methods for deciphering the kinome. Nature Methods 2: 17-25.
Bardwell L (2006) Mechanisms of MAPK signalling specificity. Biochem. Soc. Trans. 34: 837-841.
Cowan-Jacob SW (2006) Structural biology of protein tyrosine kinases. Cell Mol Life Sci. 63: 2608-2625.

Lecture Materials: Outline, Reference List, Study Questions
Presentation: Powerpoint or PDF
Quantitative Question #7 Answer

Discussion Paper: Villa F, et al. (2007) Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 8: 839-845.

28

Thursday 12/6

Phosphoprotein phosphatases. Hydrolytic reaction mechanisms. Structural basis of substrate (P-Ser/P-Thr, P-Tyr, and dual) selectivity. Phosphatase targeting subunits. Phospho-protein and phospho-proteome analysis.

Trinkle-Mulcahy L, Lamond AI (2006) Mitotic phosphatases: no longer silent partners. Curr. Opin. Cell Biol. 18: 623-631.

Swingle M, Ni L, Honkanen RE (2007) Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol Biol. 2007; 365: 23-38.

Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nature Rev. Mol. Cell Biol. 7: 833-846.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #8 Answer

Discussion Paper: Yang J, et al. (2007) The structure of Tap42/alpha4 reveals a tetratricopeptide repeat-like fold and provides insights into PP2A regulation. Biochemistry 46: 8807-8815.

29

Tuesday 12/11

Modulation of transcription by extracellular and intracellular signaling pathways. Mechanisms of regulation. Steroid hormone and related receptors. Jun-Fos, NF-kB, SRF, CREBs and ATFs, STATs, SMADs, beta-catenin, Rb and E2F.

Mertens C, Darnell JE Jr (2007) SnapShot: JAK-STAT signaling. Cell 131: 612.

Massague J, Gomis RR. (2006) The logic of TGFb signaling. FEBS Lett. 580: 2811-2820.

Wu H, Peisley A, Graef IA, Crabtree GR (2007) NFAT signaling and the invention of vertebrates. Trends Cell Biol. 17: 251-260.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #9 Answer

Discussion Paper: Dentin R, et al. (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366-369. Supp. material.

30

Thursday 12/13

The eukaryotic cell cycle. Cyclins and Cdks. Cdk inhibitors. The anaphase-promoting complex. Checkpoint controls. Molecular basis of cancer. Oncogenes, tumor suppressor genes, and regulation of cell proliferation. Apoptosis.

Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70.

Sherr CJ (2004) Principles of tumor suppression. Cell 116: 235-246.

Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr. Opin. Immunol. 19: 488-496.

Lecture Materials: Outline, Reference List, Study Questions

Presentation: Powerpoint or PDF

Quantitative Question #10 Answer

Discussion Paper: Dai C, et al. (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005-1018. Supp. material.

Wednesday 12/19

12:30pm-3:00pm

EXAM III

Location: 534 Davis Hall

Practice Exam (2006 Exam) Answer Key.

Lecture	Date	Topics	Handouts
	Tuesday 11/6	NO CLASS
21	Thursday 11/8	Nucleocytoplasmic trafficking. Nuclear pore structure. Nuclear protein import. Nuclear protein and RNA export. Regulation of nucleocytoplasmic transport. Coupling of mRNA export to transcription, splicing, and quality control mechanisms. Novel roles of karyopherins in control of mitosis and other aspects of cell regulation. Required reading: Tran EJ, Wente SR (2006) Dynamic nuclear pore complexes: life on the edge. Cell 125: 1041-1053. Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (2007) Classical nuclear localization signals: definition, function, and interaction with importin-alpha. J. Biol. Chem. 282: 5101-5105. Cole CN, Scarcelli JJ (2006) Unravelling mRNA export. Nature Cell Biol. 8: 645-647.	Lecture Materials: Outline, Reference List, Study Questions Presentation Powerpoint or PDF Quantitative Question #1 Answer Discussion Paper: Frey S, Görlich D (2007) A saturated FG-repeat hydrogel can reproduce the permeability properties of nuclear pore complexes. Cell 130: 512-523. Supp. material. A user name and password is required to access journal article pdfs and the class presentation (Powerpoint slides). You must also be logged in to a UCB server. The user name and password will be announced in Thursday's class.
22	Tuesday 11/13	Protein synthesis. Review of ribosome structure. rRNAs, tRNAs, and their modifications. Translation factors. The translation cycle. Regulation of translation. Nutrient sensing and Tor signaling. Cell size control. Required reading: Richter JD, Sonenberg N (2005) Regulation of cap-dependent translation by eIF4E inhibitory proteins. Nature 433: 477-480. Proud CG (2007) Signalling to translation: how signal transduction pathways control the protein synthetic machinery. Biochem J. 403: 217-234. Fraser CS, Doudna JA (2007) Structural and mechanistic insights into hepatitis C viral translation initiation. Nature Rev. Microbiol. 5: 29-38.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #2 Answer Discussion Paper: LaRonde-LeBlanc N, Santhanam AN, et al. (2007) Structural basis for inhibition of translation by the tumor suppressor PDCD4. Mol. Cell Biol. 27: 147-156.
23	Thursday 11/15	Protein folding in vivo. Chaperones (major heat shock / stress proteins). DnaK(Hsp70)-DnaJ(Hsp40)-GrpE. Hsp90. Hsp104. Co-chaperones. Chaperonins (GroEL/Hsp60-GroE/Hsp10 and TRiC/CCT cages). Peptidylprolyl-cis,trans-isomerases (FKBPs, cyclophilins, Ess1/Dodo/Pin1). Introduction of disulfide bonds. Prions. Young JC, Agashe VR, Siegers K, Hartl FU (2004) Pathways of chaperone-mediated protein folding in the cytosol. Nature Rev. Mol. Cell Biol. 5: 781-791. Richter K, Reinstein J, Buchner J (2007) A Grp on the Hsp90 mechanism. Mol. Cell 28: 177-179. Horwich AL, Farr GW, Fenton WA (2006) GroEL-GroES-mediated protein folding. Chem. Rev. 106: 1917-1930.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #3 Answer Discussion Paper for Friday: Vogel M, et al. (2006) Allosteric regulation of Hsp70 chaperones involves a conserved interdomain linker. J. Biol. Chem. 281: 38705-38711.
24	Tuesday 11/20	Protein turnover. Bacterial tmRNA and C-terminal tagging. Ubiquitinylation in eukaryotes. Proteosome structure. SUMO and other ubiquitin-like modifications of proteins. Zymogen and precursor processing. Intein excision and its applications. Kerscher O, Felberbaum R, Hochstrasser M (2006) Modification of proteins by ubiquitin and ubiquitin-like proteins. Annu. Rev. Cell Dev. Biol. 22: 159-180. Harper JW, Schulman BA (2006) Structural complexity in ubiquitin recognition. Cell 124: 1133-1136. Goldberg AL (2007) Functions of the proteasome: from protein degradation and immune surveillance to cancer therapy. Biochem. Soc. Trans. 35: 12-17.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #4 Answer Discussion Paper: Schwartz, et al. (2007) The Ulp2 SUMO protease is required for cell division following termination of the DNA damage checkpoint. Mol. Cell Biol. 27: 6948-6961.
	Thursday 11/22	THANKSGIVING HOLIDAY - No class on Thursday and no discussion section on Friday
25	Tuesday 11/27	Signal transduction biochemistry. Topology and classification of cell surface receptors. Scaffolds, adaptor proteins, and modular recognition domains. Roles of lipids and ions in cell signaling. Hubbard SR, Miller WT (2007) Receptor tyrosine kinases: mechanisms of activation and signaling. Curr. Opin. Cell Biol. 19: 117-123. Pawson T (2007) Dynamic control of signaling by modular adaptor proteins. Curr. Opin. Cell Biol. 19: 112-116. Seet BT, Dikic I, Zhou MM, Pawson T (2006) Reading protein modifications with interaction domains. Nature Rev. Mol. Cell. Biol. 7: 473-483.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #5 Answer Discussion Papers: Cherezov V, et al. (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318: 1258-1265. Supp material. Rosenbaum DM, et al. (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318: 1266-1273. Supp material.
26	Thursday 11/29	Structure and regulation of G proteins. Ras and related small GTPases. Translation elongation factor EF-Tu. Heterotrimeric G proteins. GEFs, GAPs & RGS proteins. Other classes of GTP-binding proteins. Wennerberg K, Rossman KL, Der CJ (2005) The Ras superfamily at a glance. J. Cell Sci. 118: 843-846. Bos JL, Rehmann H, Wittinghofer A (2007) GEFs and GAPs: critical elements in the control of small G proteins. Cell 129: 865-877. Oldham WM, Hamm HE (2006) Structural basis of function in heterotrimeric G proteins. Quart. Rev. Biophys. 39: 117-166.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #6 Answer Discussion Paper: Ballon DR, et al. (2006) DEP-domain-mediated regulation of GPCR signaling responses. Cell 126: 1079-1093. Supp. material.
27	Tuesday 12/4	Bacterial two-component signaling systems. Prokaryotic protein kinases. Eukaryotic protein kinases. Phosphotransferase reaction mechanisms. Structural basis of phospho-acceptor (Ser/Thr, Tyr, and dual) specificity. Non-canonical protein kinases (ATM/ATR, DNA-PKcs, others). Johnson SA, Hunter T (2005) Kinomics: methods for deciphering the kinome. Nature Methods 2: 17-25. Bardwell L (2006) Mechanisms of MAPK signalling specificity. Biochem. Soc. Trans. 34: 837-841. Cowan-Jacob SW (2006) Structural biology of protein tyrosine kinases. Cell Mol Life Sci. 63: 2608-2625.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #7 Answer Discussion Paper: Villa F, et al. (2007) Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 8: 839-845.
28	Thursday 12/6	Phosphoprotein phosphatases. Hydrolytic reaction mechanisms. Structural basis of substrate (P-Ser/P-Thr, P-Tyr, and dual) selectivity. Phosphatase targeting subunits. Phospho-protein and phospho-proteome analysis. Trinkle-Mulcahy L, Lamond AI (2006) Mitotic phosphatases: no longer silent partners. Curr. Opin. Cell Biol. 18: 623-631. Swingle M, Ni L, Honkanen RE (2007) Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol Biol. 2007; 365: 23-38. Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nature Rev. Mol. Cell Biol. 7: 833-846.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #8 Answer Discussion Paper: Yang J, et al. (2007) The structure of Tap42/alpha4 reveals a tetratricopeptide repeat-like fold and provides insights into PP2A regulation. Biochemistry 46: 8807-8815.
29	Tuesday 12/11	Modulation of transcription by extracellular and intracellular signaling pathways. Mechanisms of regulation. Steroid hormone and related receptors. Jun-Fos, NF-kB, SRF, CREBs and ATFs, STATs, SMADs, beta-catenin, Rb and E2F. Mertens C, Darnell JE Jr (2007) SnapShot: JAK-STAT signaling. Cell 131: 612. Massague J, Gomis RR. (2006) The logic of TGFb signaling. FEBS Lett. 580: 2811-2820. Wu H, Peisley A, Graef IA, Crabtree GR (2007) NFAT signaling and the invention of vertebrates. Trends Cell Biol. 17: 251-260.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #9 Answer Discussion Paper: Dentin R, et al. (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366-369. Supp. material.
30	Thursday 12/13	The eukaryotic cell cycle. Cyclins and Cdks. Cdk inhibitors. The anaphase-promoting complex. Checkpoint controls. Molecular basis of cancer. Oncogenes, tumor suppressor genes, and regulation of cell proliferation. Apoptosis. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100: 57-70. Sherr CJ (2004) Principles of tumor suppression. Cell 116: 235-246. Adams JM, Cory S (2007) Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr. Opin. Immunol. 19: 488-496.	Lecture Materials: Outline, Reference List, Study Questions Presentation: Powerpoint or PDF Quantitative Question #10 Answer Discussion Paper: Dai C, et al. (2007) Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis. Cell 130: 1005-1018. Supp. material.
	Wednesday 12/19 12:30pm-3:00pm	EXAM III Location: 534 Davis Hall	Practice Exam (2006 Exam) Answer Key.