doi: 10.1074/jbc.X800009200.
Epub 2008 Aug 15.
Discovery of cellular regulation by protein degradation
Affiliations
- PMID: 18708349
- PMCID: PMC3259866
- DOI: 10.1074/jbc.X800009200
Item in Clipboard
Discovery of cellular regulation by protein degradation
J Biol Chem.
.
No abstract available
Figures
The multicatenane pathway of chromosome segregation
(–5).
Thick horizontal arrows denote pathways of DNA synthesis that convert
gapped or nicked DNA circles into covalently closed circles. Thin vertical
arrows denote pathways of decatenation of the intertwined daughter
chromosomes. Daughter DNA duplexes are in blue and red,
whereas parental double-stranded DNA is in green. The monomeric
(completely decatenated) and supercoiled daughter circles are also in
green, as they become parental DNA in the next round of replication
(red arrow). The A, B, and C notations of
multicatenated DNA dimers correspond to both circles relaxed (nicked or
gapped), one circle covalently closed (and therefore supercoiled), and both
circles covalently closed, respectively. Numbers, e.g.
A10–A30, are catenation linking numbers, i.e. the levels
of intertwining of double helices in the topologically linked circles. The
theta structures (replication intermediates) in brackets are diagrams
of thetas in which the parental (green) DNA is nicked and therefore
relaxed as histone-free DNA. The indicated multicatenanes such as B5,
C3, C5, etc., are not depicted explicitly, given their
highly “entangled” configurations as free DNA. Among the technical
innovations in these 1980–1981 studies
(–5)
was the discovery that hypertonic treatment of SV40-infected green monkey CV1
cells arrested replicated chromosomes at the stage of decatenation. During
arrest, highly intertwined nicked (or gapped) A-type multicatenanes were
eventually converted (via B-type intermediates) to the equally highly
intertwined C-type multicatenanes (C10–C30), in which both
circles were covalently closed and supercoiled (thick dashed arrows
at the top). The supercoiled state stemmed from the presence of nucleosomes in
the minichromosomes, prior to removal of histones for analyses of DNA
topology. Upon release from the decatenation block, the highly intertwined
C-type multicatenanes were decatenated to supercoiled monomers (vertical
dashed arrows; “recovery pathway”). The actual paths taken
during chromosome segregation (in the absence of decatenation arrest) include
the entire matrix of transitions shown in the diagram. The relative rates of
flow along specific paths depend on the rates of gap-filling DNA synthesis
(converting a nicked or gapped circle into a covalently closed circle)
versus the rates of decatenation of multiply intertwined chromosomes
by topoisomerase II (3,
4).
The Ub system of the yeast S. cerevisiae. The fundamental
design of this system is conserved among eukaryotes. The yeast Ub genes
UBI1–UBI4, two of which contain introns, encode fusions of Ub
either to itself or to one of two ribosomal proteins. These fusions are
cleaved by DUB enzymes, yielding mature Ub. Thioester bonds between Ub and the
active-site Cys residues of Ub-specific enzymes are indicated (∼). The
conjugation of Ub to other proteins involves a preliminary ATP-dependent step
in which the last residue of Ub (Gly76) is joined, via a thioester
bond, to a Cys residue of the E1 (Ub-activating) enzyme, encoded by
UBA1. The activated Ub is transferred to a Cys residue in one of
several Ub-conjugating (E2) enzymes, encoded by the UBC family genes,
and from there to a Lys residue of an ultimate acceptor protein. E2 enzymes
function as subunits of E2-E3 Ub ligase holoenzymes. The functions of E3
include the initial recognition of a substrate's degradation signal (degron)
and the E2/E3-mediated formation of substrate-linked poly-Ub chains (green
ovals). The names of some of the ∼200 E3 enzymes of S.
cerevisiae are indicated as well. A targeted ubiquitylated protein is
processively degraded to short peptides by the ATP-dependent 26 S
proteasome.
The mammalian N-end rule pathway. N-terminal residues are indicated
by single-letter abbreviations for amino acids. Yellow ovals denote
the rest of a protein substrate. A sign, above hemin in the middle of
diagram, is a modified “down-regulation” sign that denotes,
specifically, a down-regulation mediated, at least in part, by target's
degradation. C* denotes oxidized Cys, either Cys sulfinate or Cys
sulfonate, produced in reactions mediated by NO, O2, and their
derivatives. Oxidized N-terminal Cys is arginylated by ATE1-encoded
isoforms of R-transferase. Type 1 and 2 primary destabilizing N-terminal
residues are recognized by the pathway's E3 Ub ligases, called N-recognins.
Through their other substrate-binding sites, these E3 enzymes also recognize
internal (non-N-terminal) degrons in other substrates of the N-end rule
pathway, denoted by the larger oval. As shown in the diagram, hemin
(Fe3+-heme) interacts not only with ATE1 (R-transferase) but with
UBR family Ub ligases as well, and down-regulates at least some E3 enzymes of
this family (89).
References
-
- Varshavsky, A., Sundin, O., and Bohn, M. (1979) Cell 16 453–466 - PubMed
-
- Sundin, O., and Varshavsky, A. (1980) Cell 21 103–114 - PubMed
-
- Sundin, O., and Varshavsky, A. (1981) Cell 25 659–669 - PubMed
-
- Varshavsky, A., Levinger, L., Sundin, O., Barsoum, J., Özkaynak, E., Swerdlow, P., and Finley, D. (1983) Cold Spring Harb. Symp. Quant. Biol. 47 511–528 - PubMed
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