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The ubiquitin
ligase can participate in the hierarchic transfer of
ubiquitin into the substrate, or can function as an adaptor
to facilitate positioning and transfer of ubiquitin from the
E2 directly onto the substrate. A number of E3s have been
shown to physically bind to the substrate. Ubiquitination of
the target substrate occurs through linkage of thea-carboxyl
glycine of ubiquitin to a lysine e-amino group on the
protein substrate. The consecutive addition of ubiquitin
moieties to a substrate generates a polyubiquitin chain. The
nomenclature of E1, E2, and E3 came from the identification
of ubiquitin enzymes in eluates from ubiquitin affinity
columns. Both E2 and E3 proteins exist as large families and
it is thought that different combinations of E2s with
different E3 proteins define the substrate specificity.
Seventeen different E2s have been identified in both
Saccharomyces cerevisiae and many more in humans. In
contrast to the E2s, whose catalytic sites are well
conserved among themselves, only some E3 ligases share a few
motifs (e.g., the hect domain, the TPR motif, the F box, the
WD40 repeat). In particular, the hect domain defines a class
of E3s that the recent explosion of sequence information
from the various organism-based genome efforts indicates to
be remarkably large.
The 26S proteasome is composed of a catalytic 20S core of
four heptameric rings of a and b subunits stacked into a
hollow cylinder. Two 19S subunits, also called PA700,
contain 700-kDa proteasome activators and are found at the
ends of the 20S cylinder. The multi-ubiquitin side chain
both targets and tethers substrates to the S5 subunit of the
PA700. ATP-dependent unfolding of the substrate allows its
translocation through the 13 Å entrance of the 20S catalytic
channel. This latter translocation may be accompanied by
partial disassembly of the ubiquitin chains. Peptidases on
the inner surface of bsubunits degrade the substrate,
releasing ubiquitinated peptides. Ubiquitin is then recycled
by the action of deubiquitinating enzymes on these
fragments.
Proteolysis into the next Millennium
(Based on a contribution made by Professor R John Mayer,
Professor of Molecular Cell Biology, University of
Nottingham, United Kingdom, amended and edited by Dr Paul W
Sheppard, Scientific Development Director, AFFINITI Research
Products Ltd, Exeter,United Kingdom.)
1. Reflections - a waste of time and energy!
The notion that intracellular proteolysis would be of
physiological significance was widely discounted for many
years because degrading proteins after synthesis would be
"energetically-wasteful". Furthermore, the notion that the
destruction of specific proteins might be a key step in the
physiological regulation of signal transduction pathways was
also refuted: it would be necessary to make the protein
again. Prejudice in science is curious: both premises are
wrong. Proteins are degraded continuously and
non-continuously as directed by physiological need.
Intracellular proteolysis has lysosomal and non-lysosomal
components: the latter being mediated predominantly by the
ubiquitin/26S proteasome system. However,
inter-relationships might be expected between the systems
and are now starting to become apparent.
2. Intracellular proteolysis - the ultimate regulator of
proteomic function?
(i) cell cycle: the magic roundabout?
The biochemical mechanisms that regulate the cell cycle are
the subject of intense investigation. The G1/S, G2/M and
mitotic phases of the cell cycle are controlled by the
actions of cyclin-dependent kinases, kinase inhibitors,
phosphatases and ubiquitin/26S proteasome-dependent
proteolysis. Critical phosphorylation events attract
ubiquitin-protein ligases which ubiquitinylate cyclins and
kinase inhibitors in preparation for degradation by the 26S
proteasome. The SCF family of ubiquitin-protein ligases is
responsible for protein ubiquitinylation in the G1/S phase
and the related APC/cyclosome complexes perform the same
function in G2/M. The search continues for further
substrates that are targeted for degradation during the cell
cycle and cytokinesis (Pagano, 1997). Evidence is beginning
to accumulate that protein delivery to the 26S proteasome
may require more than substrate protein
multi-ubiquitinylation. Accessory or adaptor molecules may
be involved in protein binding to the 19S regulator of the
26S proteasome (Higashitsuji et al.,1999).
(ii) transcription: complexes and complexity
Transcription factors are lethal molecules: too much or too
little of these controllers of gene expression has
catastrophic consequences for the cell.
Transcription factors are degraded by the ubiquitin/26S
proteasome system. For example, the increased expression of
hypoxia-sensitive genes is controlled by hypoxia-inducible
transcription factors (HIF). HIF are degraded by the
ubiquitin/26S proteasome system. Amongst the HIF-controlled
genes are those responsible for angiogenesis. In von
Hippel-Lindau (VHL) disease, kidney tumours are associated
with increased angiogenesis. Mutations in the VHL tumour
suppressor can cause these tumours. The VHL protein is a
component of a VHL-elonginB/C/cullin2 complex similar to SCF
ubiquitin-protein ligase (Kaelin and Mather, 1998).
(iii) signal transduction: pathway terminators
Ubiquitinylation of the lymphocyte homing receptor and other
membrane receptors including growth-hormone receptor and the
platelet-derived growth factor receptor has been known for
many years. More recently, downstream adaptor proteins for
membrane receptor proteins have been shown to be
ubiquitinylated, e.g., cCbl. Receptor down-regulation by
ubiquitin-dependent degradation is an important aspect of
signal transduction. Receptor ubiquitinylation is a complex
process with mono-ubiquitinylation acting as a
internalisation signal as well as multi-ubiquitinylation
serving as the degradation signal (Hicke, 1999; Terrell et
al., 1999). Again, as in cell cycle control, it appears that
kinases, phosphatases and ubiquitin-dependent proteolysis
control key cell physiological processes.
(iv) antigen processing: bits and pieces
Although not absolutely exclusively, proteasomes control
protein fragmentation as part of MHC Class I antigen
processing. Proteins are broken down into small peptides
(9-13 amino acids) which move into the endoplasmic reticulum
(ER) where they can bind to MHC molecules and trigger export
of peptide-MHC complexes to the cell surface to activate
cytotoxic lymphocytes. Furthermore, interferon-g can cause
cells to incorporate new catalytic subunits into new 20S
proteasomes with an increased ability to generate protein
fragments to trigger a better Class I response and also
cause the expression of subunits of the 11S regulator of the
20S proteasome which, again, facilitates the production of
protein fragments which bind optimally to MHC Class I
molecules and accelerate the cytotoxic lymphocyte response (Groettrup
et al., 1997).
(v) destruction alternatives: dump or larder?
Chronic human neurodegenerative diseases are associated with
the formation of perinuclear protein aggregates (inclusions)
in neurones (Mayer et al., 1999). Similarly, during some
latent viral infections, e.g. Epstein Barr Virus (EBV),
latent membrane protein (LMP) accumulates in EBV-transformed
lymphoblastoid cells in pericentriolar inclusions (Laszlo et
al., 1991).
Recently, it has been shown that both the mutant cystic
fibrosis transmembrane regulator (CFTR) and mutant
presenilin-1 accumulate in "aggresomes" in the
pericentriolar region (Johnston et al., 1998; Wigley et al.,
1999). These aggresomes are enriched in components of the
ubiquitin/26S proteasome pathway and cell stress proteins.
Additionally, a SCF ubiquitin-protein ligase has a rôle in
centrosome duplication (Freed et al., 1999). Maybe, the
ubiquitinylation/26S proteasomal apparatus is focussed on
the pericentriolar region not only to facilitate cell
division but also to ubiquitinylate mutant proteins (and
excess wild-type proteins?) which have been removed from the
ER by the ER-quality control system (Hiller et al., 1996).
However, instead of being degraded, excised ubiquitinylated
proteins are deposited in the pericentriolar region either
simply to prevent toxic gains of function of the
ubiquitinylated proteins or for subsequent degradation by
the 26S proteasome system or the lysosomal system (Doherty
et al., 1987; Earl et al., 1987).
3. The ubiquitinylation machinery and the proteases -
Nuts and bolts
(i) ubiquitons: variations on a superfold
There are cellular proteins related to ubiquitin but
differing in terms of primary sequence and three-dimensional
structure. Furthermore, these "ubiquitons" are either free
and conjugatable or are genetically built into proteins,
e.g., RAD23 and Parkin. The key element in these molecules
is the ubiquitin-superfold and the utilisation of this
superfold for a variety of purposes during protein-protein
interactions (Mayer et al., 1998). The attachable
SUMO/Smt3p/Sentrin/Pic1/Gmp1 and NEDD8/Rub1 ubiquitons have
roles in protein-import into the nucleus (Matunis et al.,
1996) and the regulation of ubiquitin-protein ligase
activity, respectively (Liakopoulos et al., 1998). The
functions of built-in ubiquitons are less obvious, although
RAD23 has a role in nucleotide excision repair and binds to
the so-called ubiquitin binding subunit (S5a) of the 19S
regulator of the 26S proteasome (Hiyami et al., 1999).
(ii) autophagy: squaring the circle
The basis of the utilisation of ubiquitin (and attachable
ubiquitons) is the formation of an isopeptide bond between
the carboxylic acid moiety of the carboxyl-terminal glycine
residue of ubiquitin and the e-amino group of a lysine
residue within a target protein. Remarkably, the evolution
of the enzymology to generate isopeptide bonds, which link
one protein to another, might be the "commonality" in
intracellular proteolysis.
Recently, an isopeptide system has been discovered which
links proteins together as part of the mechanism of
autophagolysosome formation (Mizushima et al., 1998a, 1998b;
Shintani et al., 1999). Genes coding for enzymes with
analogous functions to a ubiquitin activating enzyme (E1)
and a ubiquitin-conjugating enzyme (E2) have been discovered
which control early events in autophagy in yeast and in man.
Given the diversity of proteins containing genetically
built-in ubiquitons, it is predictable that the autophagic
regulator protein in yeast (apg12p) which is conjugated to
another protein (apg5p) by an isopeptide-bond will have a
ubiquitin superfold: time and crystallography will tell!
(iii) ubiquitin-protein ligases: ultimate arbiters
"To be or not to be" may be part of the question: however,
ubiquitin-protein ligases are the answer!
Currently, there are two families of ubiquitin-protein
ligases: the HECT domain (homologous to the E6-accessory
protein [AP] carboxyl-terminus) enzymes (which form
thioesters with ubiquitin) and the RING finger ligases. The
E6 protein is encoded in malignant forms of papilloma
viruses and through recruitment of the cellular E6-AP
ubiquitin-protein ligase causes the degradation of p53. The
RING finger proteins are either in complexes with other
proteins essential for ligase activity (the SCF and APC/cyclosome
complexes) or are associated with putative substrate
proteins. The RING finger ubiquitin-protein ligases bind
ubiquitin-conjugating enzymes to facilitate ubiquitinylation
of target proteins. The latter group of RING finger ligases
includes c-Cbl, which is an adaptor for receptor protein
tyrosine kinases. The c-Cbl protein binds to phosphorylated
tyrosine residues in activated receptors via SH2 domains and
triggers ubiquitinylation via the associated
ubiquitin-conjugating enzyme (Joazeiro et al., 1999). Other
RING finger proteins may act as ubiquitin-protein ligases.
For example, the protein product of the breast cancer 1 gene
(BRCA1) has a RING finger and is a ubiquitin-protein ligase
(Lorick et al., 1999). At least 7 other RING finger proteins
have demonstrated ubiquitin-protein ligase activity.
There are over 400 proteins with RING fingers in the
database. These proteins could be bone fide
ubiquitin-protein ligases: there are certainly sufficient
substrates amongst the products of the 70,000-100,000 human
genes that code for proteins (O'Brien et al., 1999)!
Alternatively, evolution may have contrived a system whereby
RING finger proteins remain inactive in functional
complexes, e.g., c-Cbl, until activated, e.g. in response to
receptor tyrosine kinase ligands, when the RING finger
recruits a ubiquitin-conjugating enzyme. This
ubiquitinylates either the RING finger protein or some
putative protein substrate in the functional complex (Lorick
et al., 1999). Either way, the ubiquitin-conjugating enzyme
becomes active.
(iv) non-lysine48-linked ubiquitin chains: which and why?
Ubiquitin molecules, which are linked together in chains to
a protein as a degradation signal, are covalently coupled
via an isopeptide bond as described earlier utilising the
lysine48 (K48) residue of each ubiquitin. However, chains
have also been shown to be linked via four of the other six
lysines in ubiquitin (K6,K11, K29, and K63). The K63-linked
polyubiquitin chains appear to play a role in DNA repair.
The formation of K63-linked chains is not a signal for
degradation, which means that attachment of K63-linked
chains to proteins (if this is a widespread process?) is not
for degradation but for some other purpose, probably in the
nucleus in DNA repair. The generation of K63-linked chains
is through a heterodimer composed of an
ubiquitin-conjugating enzyme variant (UEV) and a specific
ubiquitin-conjugating enzyme, ubp13p (Hofmann and Pickart,
1999). The UEV proteins are homologous to
ubiquitin-conjugating enzymes but lack the critical
catalytic cysteine residue. The UEV proteins have been
implicated in cell transformation and tumour suppression.
Again a protein, the ubiquitin-conjugating enzyme variant,
activates an ubiquitin-conjugating enzyme. How often will
ubiquitin-conjugating enzymes be found to be complexed to
other proteins in order to be active?
(v) proteasome interaction partners: friends and foes
Many cellular and viral proteins have been shown to interact
with both 20S and 19S proteasomal subunits. The six
non-redundant ATPases of the 19S regulator, which sit as a
"collar" (base) along with two non-ATPases on each end of
the 26S proteasome, have been shown to interact with many
cellular and viral proteins. Presumably, these interactions
are to modulate the recognition/degradation of either the
binding proteins themselves or other cellular and viral
proteins. For example, the HEC protein (highly expressed in
cancer) specifically interacts with the S7 ATPase and
modulates the degradation of a mitotic cyclin (Chen et al.,
1997), whilst the papilloma virus E7 protein specifically
interacts with the S4 ATPase and controls the degradation of
the retinoblastoma protein (Boyer et al., 1996; Berezutskaya
and Bagchi, 1997). Recently, a cellular protein, gankyrin,
which interacts with the S6 ATPase, has been discovered to
be an oncoprotein which increases the degradation of the
retinoblastoma protein (Higashitsuji et al., 2000). Perhaps,
E7 mimics gankyrin?
(vi) proteasome assembly: THE Millennium structure
The assembly of the 20S core of the 26S proteasome has been
solved in part by studies in Thermoplasma (Lupas et al.,
1997) and other organisms (Schmidtke et al., 1996). However,
the details of the assembly of the heptameric a-rings and
the role of the heptameric b-rings in 20S particle formation
has yet to be fully resolved. Some a-subunits, e.g., a7 (C8)
may have co-ordinating roles for the assembly of the
heptameric a-rings (Gerards et al., 1998). The mode of
assembly of the 19S regulators of the 26S proteasome is
poorly understood, although the elegant demonstration that
the 19S regulator consists of a "base" containing the six
ATPases and two other proteins, with the other regulatory
proteins in the "lid", helps to clarify the basic structural
features of the 19S complex on which to build details of the
assembly process (Glickman et al., 1998).
(vii) deubiquitinating enzymes: more yin than yang
The sequencing of the yeast genome has revealed that there
are more genes coding for deubiquitinating enzymes than
ubiquitin-conjugating enzymes; the precise functions of
these enzymes are unknown but several of the enzymes are
functionally non-redundant. Deubiquitinating enzymes are
crucial for cellular proteolysis including ubiquitin-chain
disassembly (Amerik et al., 1997) and ubiquitin
chain-editing by the 26S proteasome (Lam et al., 1997).
Deubiquitinating enzymes have key roles in cell cycle
regulation (Zhu et al., 1996, 1997) and interact with the
BRCA1 protein (Jensen et al., 1998), which appear to be one
of the RING finger ubiquitin-protein ligases (Lorick et al.,
1999), perhaps in some large complex involving DNA repair
and protein ubiquitinylation (see iii above) and
deubiquitinylation. Clearly, these enzymes will have
important roles in cellular physiology in addition to the
ubiquitin-conjugating pathway.
(viii) tripeptidyl peptidases: back to basics
The ubiquitin/26S proteasome system can degrade proteins to
small peptides. There must be one or more enzyme systems
that can then produce the basic building blocks of proteins,
the amino acids, from such peptides. One strong candidate is
tripeptidyl peptidase, also a megaprotein complex, capable
of cleaving a variety of peptides into tripeptides for
further excision into amino acids by exopeptidases (Tomkinson,
1999). Other enzymes may assist in the total degradation of
proteins into amino acids and their full characterisation is
keenly awaited.
(ix) substitutes: key players in the game
Evolution enjoys compensation by substitution. Clones of
cells deprived of the activity of 20S proteasomes by
inhibition with, for example, lactacystin can survive by
using another protease to degrade proteins and process
antigens (Glas et al., 1998). The compensatory protease may
be the gigantic compartmentalised tricorn protease (Tamura
et al., 1998). The full significance of this protease
complex is yet to be determined.
4. Prospects - hear today and here tomorrow
Intracellular proteolysis is the most recently discovered
regulatory system of cellular physiology. The field has
undergone a Cinderella-like "rags to riches" growth in the
last five years. Predictably, within the next five years,
driven by genomics and proteomics, not to mention good
old-fashioned biochemistry - would that be functional
genomics?! - everything from cell division, development and
differentiation to cellular senescence will be found to have
a proteolytic component. There is no simpler way to stop a
physiological process than to destroy one of the components
of a pathway in a controlled fashion. Already, a keen
interplay between phosphorylation, ubiquitinylation and
degradation can be seen (Montagnoli et al., 1999).
Ubiquitinylation will support and rival phosphorylation in
the regulation of the life process. After all, what is the
conceptual difference between the addition and removal of
phosphates or acyl-groups? It now appears that acetylation
controls transcription (Brehm et al., 1999) whilst
ubiquitinylation not only contributes to the control of
transcription but modulates a host of other cell
physiological processes as well.
|
5. References -
who's done what, when, and with whom?
Amerik, A. Y., Swaminathan, S., Krantz, B. A., Wilkinson, K.
D., and Hochstrasser, M. (1997). In vivo disassembly of free
polyubiquitin chains by yeast Ubp14 modulates rates of
protein degradation by the proteasome. EMBO J. 16,
4826-4838.
Berezutskaya, E., and Bagchi, S. (1997). The human papilloma
virus E7 oncoprotein functionally interacts with the S4
subunit of the 26S proteasome. J. Biol. Chem. 272,
30135-30140.
Boyer, S. N., Wazer, D. E., and Band, V. (1996). E7 protein
of human papilloma virus-16 induces degradation of
retinoblastoma protein through the ubiquitin-proteasome
pathway. Cancer Res. 56, 4620-4624.
Brehm, A., Miska, E., Reid, J., Bannister, A., and
Kouzarides, T. (1999). The cell cycle-regulating
transcription factors E2F-RB. Brit. J. Cancer (Supplement 1)
80, 38-41.
Chen, Y., Sharp, D., and Lee, W.-H. (1997). HEC binds to the
seventh regulatory subunit of the 26S proteasome and
modulates the proteolysis of mitotic cyclins. J. Biol. Chem.
272, 24081-24087.
Doherty, F. J., Wassell, J. A., and Mayer, R. J. (1987). A
putative protein-sequestration site involving intermediate
filaments for protein degradation by autophagy. Studies with
microinjected purified glycolytic enzymes in 3T3-L1 cells.
Biochem. J. 241, 793-800.
Earl, R. T., Mangiapane, E. H., Billett, E. E., and Mayer,
R. J. (1987). A putative protein-sequestration site
involving intermediate filaments for protein degradation by
autophagy. Biochem. J. 241, 809-815.
Freed, E., Lacey, K. R., Huie, P., Lyapina, S. A., Deshaies,
R. J., Stearns, T., and Jackson, P. K. (1999). Components of
an SCF ubiquitin ligase localise to the centrososme and
regulate the centrosome duplication cycle. Genes and
Develop. 13, 2242-2257.
Gerards, W. L. H., deJong, W. w., Bloemendal, H., and
Boelens, W. (19998). The human proteasomal subunit HSC8
induces ring formation of another a-type subunits. J. Mol.
Biol. 275, 113-121.
Glas, R., Bogyo, M., McMaster, J. S., Gaczynska, M., and
Ploegh, H. L. (1998). A proteolytic system that compensates
for loss of proteasome function. Nature 392, 618-622.
Glickman, M. H., Rubin, D. M., Coux, O., Wefes, I., Pfeifer,
G., Cjeka, Z., Baumeister, W., Fried, V. A., and Finley, D.
(1998). A subcomplex of the proteasome regulatory particle
required for ubiquitin conjugate degradation and related to
the COP-9-signalasome and eIF3. Cell 94, 615-623.
Groettrup, M., Soza, A., Schmidtke, G., Kuckelkorn, U.,
Theobald, M., Eggers, M., Ruppert, T., Koszinowski, U., and
Kloetzel, P. M. (1997). The regulation of proteasomal MHC
class I antigen processing activity. Cancer Gene Therapy 4,
308-309.
Hicke, L. (1999). Gettin' down with ubiquitin: turning off
cell-surface receptors, transporters and chanels. Trends in
Cell Biol. 9, 107-112.
Higashitsuji, H., Itoh, K., Nagao, T., Dawson, S., Nonoguchi,
K., Kido, T., Mayer, R. J., Arrii, S., and Fujita, J.
(2000). Reduced stability of retinoblatoma protein by
gankyrin, an oncogenic ankyrin-repeat protein overexpressed
in hepatomas. Nature Medicine 6, 96-99.
Hiller, M. M., Finger, A., Schweiger, M., and Wolf, D. H.
(1996). ER Degradation of a Misfolded Luminal Protein by the
Cytosolic Ubiquitin-Proteasome Pathway. Science 273,
1725-1728.
Hiyami, H., Yokoi, M., Masutani, C., Sugasawa, K., Maekawa,
T., Tanaka, K., Hoeijmakers, J. H. J., and Hanaoka, F.
(1999). Interaction of hHR23 with S5a. J. Biol.Chem. 274,
28019-28025.
Hofmann, R. M., and Pickart, C. M. (1999). Noncanonical
MMS2-encoded ubiquitin-conjugating enzyme functions in
assembly of novel polyubiquitin chains for DNA repair. Cell
96, 645-653.
Jensen, D. E., Proctor, M., Marquis, S. T., Gardner, H. P.,
Ha, S. I., Chodosh, L. A., Ishov, A. M., Tommerup, N.,
Vissing, H., Sekido, Y., and others. (1998). BAP1: a novel
ubiquitin hydrolase which binds to the BRCA1 RING finger and
enhances BRCA1-mediated cell growth suppression. Oncogene
16, 1097-1112.
Joazeiro, C. A. P., Wing, S. S., Huang, H.-K., Leverson, J.
D., Hunter, T., and Liu, Y.-C. (1999). The tyrosine kinase
negative regulator c-Cbl as a RING-type E2-dependent
ubiquitin-protein ligase. Science 286, 309-312.
Johnston, J. A., Ward, C. L., and Kopito, R. R. (1998).
Aggresomes: a cellular response to misfolded proteins. J.
Cell Biol.143, 1883-1898.
Kaelin, W. G., and Mather, E. R. (1998). The VHL tumour-suppressor
gene paradigm. Trends in Genetics 14, 423-426.
Lam, Y. A., Xu, W., DeMartino, G. N., and Cohen, R. E.
(1997). Editing of ubiquitin conjugates by an isopeptidase
in the 26S proteasome. Nature 385, 737-740.
Laszlo, L., Tuckwell, J., Self, T., Lowe, J., Landon, M.,
Smith, S., Hawthorne, J. N., and Mayer, R. J. (1991). The
latent membrane protein-1 in Epstein-Barr Virus-transformed
lymphoblastoid cells is found with ubiquitin - protein
conjugates and heat-shock protein-70 in lysosomes oriented
around the microtubule organizing centre. J. Pathol. 164,
203-214.
Liakopoulos, D., Doenges, G., Matuschewski, K., and Jentsch,
S. (1998). A novel protein modification pathway related to
the ubiquitin system. EMBO J. 17, 2208-2214.
Lorick, K. L., Jensen, J. P., Fang, S., Ong, A. M.,
Hatakeyama, S., and Weissman, A. M. (1999). RING fingers
mediate ubiquitin-conjugating enzyme (E2)-dependent
ubiquitination. Proc. Natl. Acad. Sci. 96, 11364-11369.
Lupas, A., Flanagan, J. M., Tamura, T., and Baumeister, W.
(1997). Self-compartmentalizing proteases. Trends In
Biochemical Sciences 22, 399-404.
Matunis, M. J., Coutavas, E., and Blobel, G. (1996). A novel
ubiquitin-like modification modulates the partitioning of
the Ran-GTPase-activating protein RanGAP1 between the
cytosol and the nuclear pore complex. J. Cell Biol. 135,
1457-1470.
Mayer, R. J., Landon, M., and Layfield, R. (1998). Ubiquitin
superfolds: intrinsic and attachable regulators of cellular
activities. Folding and Design 3, R97-R99.
Mayer, R. J., Landon, M., Lowe, J., Fergusson, J., Walker,
G., Dawson, S., Layfield, R., and Arnold, J. (1999).
Ubiquitin, proteasomes and neurodegenerative disease. In
Proteasomes, D. Wolf and W. Hilt, eds. (Berlin: Springer-Verlag)
in press.
Mizushima, N., Noda, T., Yoshimori, T., Tanaka, Y., Ishii,
T., George, M. D., Klionsky, D. J., Ohsumi, M., and Ohsumi,
Y. (1998a). A protein conjugation system essential for
autophagy. Nature 395, 395-398.
Mizushima, N., Sugita, H., Yoshimori, T., and Ohsumi, Y.
(1998b). A new protein conjugation system in human. J. Biol.
Chem. 273, 33889-33892.
Montagnoli, A., Fiore, F., Eytan, E., Carrano, A. C.,
Draetta, G., Hershko, A., and Pagano, M. (1999).
Ubiquitination of p27 is regulated by Cdk-dependent
phosphorylation and trimeric complex formation. Genes &
Development 13: 1181-1189.
O'Brien, S.J., Menotti-Raymond, M., Murphy, W.J., Nash, W.G.,
Wienberg, J., Stanyon, R., Copeland, N.G., Jenkins, N.A.,
Womack, J.E., Marshall Graves, J.A. (1999). The promise of
comparative genomics in mammals. Science 286, 458-481.
Pagano, M.(1997). Regulation of cell cycle regulatory
proteins by the ubiquitin pathway. FASEB J 11, 1067-1075.
Schmidtke, G., Kraft, R., Kostka, S., Henklein, P., Frommel,
C., Lowe, J., Huber, R., Kloetzel, P. M., and Schmidt, M.
(1996). Analysis of mammalian 20S proteasome biogenesis: the
maturation of ß-subunits is an ordered two-step mechanism
involving autocatalyis. EMBO J. 15, 6887-6898.
Shintani, T., Mizushima, N., Ogawa, Y., Matsuura, A., Noda,
T., and Ohsumi, Y. (1999). Apg10p, a novel
protein-conjugating enzyme essential for autophagy in yeast.
EMBO J. 18, 5234-5241.
Tamura, N., Lottspeich, F., Baumeister, W., and Tamura, T.
(1998). The role of tricorn protease and its aminopeptidase-interacting
factors in cellular protein degradation. Cell 95, 637-648.
Terrell, J., Shih, S., Dunn, R., and Hicke, L. (1999). A
function for monoubiquitination in the internalisation of a
G protein-coupled receptor. Mol. Cell 1, 193-202.
Tomkinson, B. (1999). Tripeptidyl peptidases: enzymes that
count. Trends in Biochemical Sciences 24, 355-359.
Wigley, W. C., Fabunmi, R. P., Lee, M. G., Marino, C. R.,
Muallem, S., DeMartino, G. N., and Thomas, P. J. (1999).
Dynamic association of proteasomal machinery with the
centrosome. J. Cell Biol. 145, 481-490.
Zhu, Y., Carroll, M., Papa, F. R., Hochstrasser, M., and
D'andrea, A. D. (1996). DUB-1, A deubiquitinating enzyme
with growth-suppressing activity. Proc.Natl Acad. Sci. 93,
3275-3279.
Zhu, Y. A., Lambert, K., Corles, C., Copeland, N. G.,
Gilbert, D. J., Jenkins, N. A., and D'Andrea, A. D. (1997).
DUB-2 is a member of a novel family of cytokine-inducible
deubiquitinating enzymes. J. Biol. Chem. 272, 51-57.
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