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Allosteric activation of the ubiquit...

Du, Fangyong.

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Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions./
Author:	Du, Fangyong.
Description:	195 p.
Notes:	Adviser: Alex Varshavsky.
Contained By:	Dissertation Abstracts International63-04B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3049146
ISBN:	0493635424

Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions.
Du, Fangyong.

Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions. - 195 p.

Adviser: Alex Varshavsky.

Thesis (Ph.D.)--California Institute of Technology, 2002.

The N-end rule relates the <italic>in vivo</italic> half life of a protein to the identity of its N-terminal residue. UBR1, the E3 of the N-end rule pathway in <italic>Saccharomyces cerevisiae</italic>, targets proteins that bear destabilizing N-terminal residues for Ub-dependent, processive degradation. UBR1 binds protein substrates or dipetides through two distinct sites: the type 1 site, specific for basic residues, and the type 2 site, specific for bulky hydrophobic residues. UBR1 also recognizes an internal degradation signal of the 35 kDa homeodomain protein CUP9, a transcriptional repressor of the di- and tripeptide transporter PTR2.

ISBN: 0493635424Subjects--Topical Terms:

1017730
Biology, Genetics.

Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions.
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008 110425s2002 eng d
020 $a 0493635424
035 $a (UnM)AAI3049146
035 $a AAI3049146
040 $a UnM $c UnM
100 1 $a Du, Fangyong. $3 1251287
245 1 0 $a Allosteric activation of the ubiquitin ligase UBR1 by short peptides: Molecular mechanisms and physiological functions.
300 $a 195 p.
500 $a Adviser: Alex Varshavsky.
500 $a Source: Dissertation Abstracts International, Volume: 63-04, Section: B, page: 1696.
502 $a Thesis (Ph.D.)--California Institute of Technology, 2002.
520 $a The N-end rule relates the <italic>in vivo</italic> half life of a protein to the identity of its N-terminal residue. UBR1, the E3 of the N-end rule pathway in <italic>Saccharomyces cerevisiae</italic>, targets proteins that bear destabilizing N-terminal residues for Ub-dependent, processive degradation. UBR1 binds protein substrates or dipetides through two distinct sites: the type 1 site, specific for basic residues, and the type 2 site, specific for bulky hydrophobic residues. UBR1 also recognizes an internal degradation signal of the 35 kDa homeodomain protein CUP9, a transcriptional repressor of the di- and tripeptide transporter PTR2.
520 $a Here I report that the internal degradation signal of CUP9 is recognized by UBR1 through its third, distinct substrate-binding site. Occupation of the type 1 or type 2 sites of UBR1 by dipeptides allosterically stimulates the UBR1-dependent multi-ubiquitylation of CUP9 in an <italic>in vitro</italic> system, which consists of purified components of the yeast N-end rule pathway. UBR1 is the first E3 shown to be allosterically regulated by small compounds. This regulation underlies, <italic>in vivo</italic>, the accelerated UBR1-dependent degradation of CUP9 in the presence of dipeptides with destabilizing N-terminal residues. The result is a postive feedback circuit that controls the peptide import in <italic>S. cerevisiae</italic>. Specifically, the imported dipeptides bind to UBR1 and accelerate the UBR1-dependent degradation of CUP9, thereby derepressing the transcription of <italic>PTR2</italic> and increasing the cell's capacity to import peptides.
520 $a I also describe a new, autoinhibition-based molecular mechanism underlying the activation of UBR1 by dipeptides. UBR1 is an autoinhibited protein, in that the binding of dipeptides to the type 1 and type 2 sites of UBR1 enhances the dissociation of the C-terminal autoinhibitory domain of UBR1 from its substrate-battling N-terminal region. Moreover, this dissociation, which allows the interaction between UBR1 and CUP9, is strongly increased only if <underline> both</underline> type 1 and type 2 sites of UBR1 are occupied by dipeptides. An autoinhibitory mechanism discovered in the <italic>S. cerevisiae</italic> UBR1 is likely to recur in metazoan homologs of UBR1, and may also be involved in controlling the activity of other Ub-dependent pathways.
590 $a School code: 0037.
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Microbiology. $3 1017734
650 4 $a Biology, Molecular. $3 1017719
690 $a 0307
690 $a 0369
690 $a 0410
710 2 0 $a California Institute of Technology. $3 726902
773 0 $t Dissertation Abstracts International $g 63-04B.
790 $a 0037
790 1 0 $a Varshavsky, Alex, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3049146