단백질분해기작의 융합오믹스 연구

연세대학교
Jurgen Roth

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자연과학 >생물ㆍ화학ㆍ환경 >생명과학
강의학기

2011년도 2학기

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Introduction

차시별 강의

1.	Introduction	Introduction is given to the entire content of the lecture series, and which books are used and that Refswork can be used to download the slides presented during the lectures. An overview is given about the principal techniques used to study the early secretory pathway and cellular digestive systems.
	Endoplasmic reticulum: Structural domains, domain formation and function	Cell and organ-specific quantitative aspects/differences for the ER are discussed. The ER domains nuclear envelope and rough ER are presented in terms of structure and function as well pathological changes due to protein accumulation and their consequences.
2.	Hu J, et al.: Membrane proteins of the endoplasmic reticulum induce high-curvature tubules. Science 319:1247, 2008	Presentation and discusssion of a scientific publication on the role of morphogenic proteins for the formation and maintenance of the shape of the rough and smooth endoplasmic reticulum domains.
	Endoplasmic reticulum:Quality control of protein folding and assembly, protein folding disorders,chemical chaperones, congenital disorders of glycosylation	House keeping function of protein quality control.Quality control of protein folding under conditions of excess of misfolded glycoproteins. Recognition and retention of misfolded glycoproteins in the endoplasmic reticulum and pre Golgi intermediates. Glycocodes for protein folding. Calnexin/calreticulin cycle. Importance of EDEM1 and OS-9 for dislocation.
	Endoplasmic reticulum:Quality control of protein folding and assembly, protein folding disorders,chemical chaperones, congenital disorders of glycosylation	Types of protein folding disorders. Definition, classes, properties and use of synthetic chaperones in protein folding disorders. Alpha-galactosidase A competitive inhibitor for Fabry disease. Phenylbutyric acid as chemical chaperone for myocilin-induced glaucoma. Definition and characterization of loss-of-function and pathological gain-of-function folding disorders.
3.	Endoplasmic reticulum:Quality control of protein folding and assembly, protein folding disorders,chemical chaperones, congenital disorders of glycosylation	Definition of glycocode for dislocation and degradation of misfolded glycoproteins generated by ER mannosidase I and II. Morphological changes due to the presence of excess of misfolded luminal glycoproteins. ER dilatation and Russel bodies, aggresome formation, Mallory bodies, and elargenment of pre-Golgi intermediates. Functional changes due to escess of misfolded glycoproteins result in unfolded protein response by activation of the Perk, ATF6 and IRE1 pathways. Role of BiP in activating the UPR. Mechanism of IRE activation. PERK activation and initiation of inflammation. ATF6 activation and acute phase response.
	Endoplasmic reticulum:Quality control of protein folding and assembly, protein folding disorders,chemical chaperones, congenital disorders of glycosylation	Dislocation of misfolded glycoproteins by ERAD-L, ERAD-M and ERAD-C. Molecular machines generated by dislocation machinery proteins. Structure and function of EDEM 1 and OS9 for protein dislocation. Mechanism of ubiquitination and dislocation of misfolded glycoproteins. Proteasomal and autophagic degradation. Diseases of glycosylation with emphasis on molecular basis , diagnostic and therapy of congenital diseases of glycosylation.
	Grove DE, et al.: Mechanisms for rescue of correctable folding defects in CFTR ΔF508. Mol Biol Cell 20:4059, 2009	Presentation and discussion of a scientific publication on the rescue of misfolded chloride channels
4.	Transitional endoplasmic reticulum and pre-Golgi intermediates: COP proteins, ER - Golgi transport, COP protein disorders	Structure of pre-Golgi intermediates and transport by microtubules. Function of pre-Golgi intermediates in vesicular transport from ER to Golgi apparatus. Transitional elements of the ER and formation of COPII coat and COPII vesicles.
	Transitional endoplasmic reticulum and pre-Golgi intermediates: COP proteins, ER - Golgi transport, COP protein disorders	COPII coat disassembly by Sec23A. Microtubule-mediated ER-to-Golgi apparatus transport of COPII vesicles. Molecular aspects of cargo transport depending on size of cargo. Types of receptor-mediated cargo transport to Golgi apparatus. Mutations of COPII proteins and resulting human lipid adsorption and craniofacial diseases.
	Li et al.: Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering.Proc Natl Acad Sci U S A 107: 16113, 2010.	Presentation and discussion of a publication on ER stress induced function of IRE1
5.	Microtubules, endoplasmic reticulum and Golgi apparatus: experimental manipulation of membrane traffic	Organization and structure of the microtubule network by centrioles. Principles of interorganelle transport of cargo. Organization of the ER and the Golgi apparatus structure by microtubules and involvement of motor proteins. Microtubule- mediated formation of aggresomes from misfolded proteins.
	Microtubules, endoplasmic reticulum and Golgi apparatus: experimental manipulation of membrane traffic	Disassembly of ER and Golgi apparatus by microtubule-depolymerizing drugs. Interference with COPII vesicular transport by Sar1 and Sec23 mutants. Blocking transport in the ER, Golgi and TGN by lowering temperature. Importance of membrane fluidity and lipid composition for vesicular transport. Blocking Golgi transport by monensin, illmaquine, and brefeldin A. Blocking transport by ATP depletion.
6.	Friedman, J. R., et al.: ER sliding dynamics and ER-mitochondrial contacts occur on acetylated microtubules. J Cell Biol 190: 363-375, 2010	Presentation and discussion of a scientific publication on organelle transport along microtubules
	Lysosomes: Structure and biosynthesis, M6P receptors and sorting	Enzymatic composition and general function of lysosomes. Light microscopical detection techniques for lysosomes. Histochemical stains for lysosome identification by electron microscopy. Structure-function relatiuonship of lysosomes by electron microscopy and residual bodies. Models for biogenesis of lysosomes. Experimental tools to modify the function of lysosomes.
7.	Boonen et al. (2009). Mice Lacking Mannose 6-Phosphate Uncovering Enzyme Activity Have a Milder Phenotype than Mice Deficient for N-Acetylglucosamine-1-Phosphotransferase Activity. Mol Biol Cell 20, 4381	Presentation and discussion of a scientific publication on defective synthesis of lysosomal mannose 6-phsphate recognition marker.
	Lysosomes: Biological significance, lysosomal disorders	Sorting of lysosomal enzymes in the TGN by MRP into primary lysosomes. PH-dependency of lysosomal enzyme - MRP interaction. Properties of lysosomal limiting membrane for acidification by proton pump. Molecular architecture of lysosomal V-ATPase. Biological significance of lysosomal digestion.
8.	Autophagy:Origin of autophagosomes, formation of autolysosomes, biological significance of autophagybiogenesis of autophagosomes, markers of autophagy	Definition and biological importance of autophagy. Biogenesis of autophagosomes and Atg proteins. Marker proteins for the isolation membrane and nucleation. Maturation of isolation membrane in autophagosomes. Tools to detect autopghagosomes by immunocytochemistry and Western blotting. Origin of the isolation membrane and the importance of the endoplasmic reticulum and omegasomes. Maturation of autophagosomes into autolysosomes: biochemistry and electron microscopy.
	Autophagy:Origin of autophagosomes, formation of autolysosomes, biological significance of autophagybiogenesis of autophagosomes, markers of autophagy	Definition and molecular biology of macroautophagy. Induction of macroautophagy by starvation and importance of mTOR. Selective autophagy of organelles and protein aggregates. p62, NBR1 and Alfy cargo receptors for selelctive autophagy. Selective autophagy of peroxisomes by pexophagy, of mitochondria by mitophagy, of endoplasmic reticulum by ER-phagy, of ribosomes by ribo-phagy and of secretory granules by crinophagy. Selective autophagy in infection and role of autophagy in cancer development. Experimental manipulation of autophagy by inhibitors and stimulators.
9.	Autophagy:molecular mechanisms of selective autophagyy	Definition and biological importance of autophagy. Biogenesis of autophagosomes and Atg proteins. Marker proteins for the isolation membrane and nucleation. Maturation of isolation membrane in autophagosomes. Tools to detect autopghagosomes by immunocytochemistry and Western blotting. Origin of the isolation membrane and the importance of the endoplasmic reticulum and omegasomes. Maturation of autophagosomes into autolysosomes: biochemistry and electron microscopy.
	Autophagy:selective autophagy of organelles and protein aggregates	pexophagy, mitophagy, crinophagy, ER-phagy, inclusion body-autophagy
10.	Hara et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.Nature 441, 885	Presentation and discussion of a scientific publication on the importance of basal autophagy for the normal functioning of brain
	Proteasome: Molecular assembly and structure, recognition and degradation of glycoproteins, regulation of short lived cytosolic and nuclear proteins, proteasome inhibitors	The functional and phylogenetic relationship between lysosomes, autophagy and proteasomes. The structure and function of the different alpha and beta type subunits of proteasomes and the assembly of the 20S proteasome. Molecular structure and function of the ante and central chambers of the 20S proteasome. Comparison with other self-compartmentalized proteases. Assembly of the 26S proteasome and recognition mechanism of substrates and mechanism of proteolytic degradation. The 11S caps.
11.	Selected examples of the function of cell surface glycans in normal and diseased state	Pathway of N-glycosyation of proteins and structural diversity of glycans depending on cell type and tissues, development and differentiation.
	Selected examples of the function of cell surface glycans in normal and diseased state	Differential cell-type distribution of sialic acids and polysialic acids in kidney, intestine and brain, their molecular basis and relation to cancer and metastasis.