Download 1984 BS, Seoul National University, Korea

YONG TAE KWON, PH.D.
AFFILIATION
Department of Biomedical Sciences and Protein Metabolism Medical
Research Center, Seoul National University College of Medicine
103 Daehakro, Jongnogu 110-799, Korea
Tel: +82-2-740-8547; Fax: +82-2-3673-2167
E-MAIL: [email protected]
ACADEMIC EDUCATION
1984 B.S., Seoul National University, Korea
1986 M.S., Seoul National University, Korea
1993 Ph.D., Seoul National University, Korea
RESEARCH & PROFESSIONAL EXPERIENCE
1994~1997
1997-2002
2002-2008
2008-2013
2010-2013
2013-present
2014-present
Postdoctoral Fellow, California Institute of Technology, CA, USA
Research Fellow, Senior Scientist, Key Staff, Caltech
Assistant Professor, School of Pharmacy, University of Pittsburgh
Associate Professor, School of Pharmacy, University of Pittsburgh
WCU Professor, Seoul National University
Professor, Department of Biomedical Sciences, Seoul National University
Director, Protein Metabolism Medical Research Center,
Seoul National University (With Aaron Ciechanover)
RESEARCH INTEREST
1. Regulated protein degradation by the ubiquitin-proteasome system
2. Proteolysis by the autophagy-lysosome system
3. Developing small molecules that regulate proteolysis in diseases
RECENT SELECTED PUBLICATIONS
1.
Cha-Molstad H.J. et al. (2015) N-terminal arginylation targets endoplasmic reticulum
chaperone BiP to autophagy through p62 binding. Nat. Cell Biol. 17:917-929.
2. Kravtsova-Ivantsiv Y. et al. (2015) The ubiquitin ligase KPC1 promotes processing of
p105 NF-κB1 to p50, eliciting strong tumor suppression. Cell 161:333-347.
3. Ciechanover, A and Y.T. Kwon. (2015) Degradation of misfolded proteins in
neurodegenerative diseases: therapeutic targets and strategies. Exp. Mo. Med. (in press)
4. Tasaki, T. et al. (2013) UBR4, an N-recognin of the N-end rule pathway, and its role in
yolk sac vascular development and autophagy. Proc. Natl. Acad. Sci. USA 110:38003805.
5. Kim, S.T. et al. (2013) Autophagy 9:1100-1103.
6. Tasaki, T. at al. (2012) The N-end rule pathway. Ann. Rev. Biochem. 81:261-289.
7. Sriram, S.M. et al. (2011) The N-end rule pathway: emerging functions and molecular
principles of substrate recognition. Nat. Rev. Mol. Cell. Biol. 12:735-747.
8. Lee, M.J. et al. (2012) Characterization of the arginylation branch of the N-end rule
pathway in G-protein-mediated proliferation and signaling of cardiomyocytes. J. Biol.
Chem. 287:24043-24052.
9. Sriram, S.M. and Y.T. Kwon (2010) The molecular principles of N-end rule recognition.
Nat. Struct. Mol. Biol. 17:1164-1165.
10. An, J.Y. et al. (2010) UBR2 mediates transcriptional silencing during spermatogenesis
via histone ubiquitination. Proc. Natl. Acad. Sci. USA. 107:1912-1917.
1
The N-end rule proteolytic pathway in regulation of p62-dependent autophagy and
autophagic protein degradation
The N-end rule pathway is a proteolytic system in which destabilizing N-terminal residues of
short-lived proteins function as a class of degradation signals (degrons), called N-degrons. Ndegrons are recognized by specific recognition components, such as ubiquitin ligases which
mediate ubiquitination, leading to selective proteolysis by the proteasome. Destabilizing
residues of the N-end rule pathway include the N-terminal arginine (Arg) residue which can
be post-translationally created by ATE1-encoded Arg-tRNA transferases (R-transferases) that
transfer the amino acid L-Arg from Arg-tRNAArg to the N-termini. Recognins that recognize
the N-terminal Arg residue of N-end rule substrates include the UBR box of a family of
proteins, called UBR box proteins. A number of cytosolic and nuclear proteins have been
shown to be targeted through the activity of their N-terminal residues as proteasomal degrons
in various biological processes. In this lecture, I will overview the functions and mechanisms
of this unique proteolytic system, with an emphasis on components and hierarchical
structures, substrates, substrate recognition, and the link to human genetic diseases. The
topics also include our recent discovery that a set of endoplasmic reticulum (ER)-residing
proteins are N-terminally arginylated, leading to cytosolic accumulation of N-terminally
arginylated ER proteins, including BiP/GRP78. Arginylated BiP (R-BiP) is associated with
misfolded proteins in stressed cytosol and binds to p62 through its N-terminal Arg residue as
an activating ligand, leading to allosteric activation, aggregation, and delivery of cargoloaded p62 to autophagosomes. By developing small molecular ligands to p62, we propose
that N-end rule ligands may be used as a therapeutic means to activate autophagic removal of
cytotoxic materials, such as pathogenic protein aggregates, from degenerating neurons.
Keywords: The N-end rule pathway, proteasome, autophagy, N-terminal arginylation,
p62, protein aggregation, neurodegenerative diseases
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