The Ubiquitin System: past, present and future perspectives : Yeo Joon Yoon
Division of Nano Sciences and Department of Chemistry
Ewha Womans University The Ubiquitin System: past, present and future perspectives November 30, 2004
Slide2 : The Novel Prize
Slide3 : By the terms of Alfred Nobel’s will the Nobel Prizes in Physics and Chemistry have been awarded by the Academy since 1901. The awarding ceremony takes place on 10 December, the anniversary of Alfred Nobel’s death. The Nobel Prize
Slide4 : the discoveries and achievements that have resulted from investigations of matter and the processes of life.
Starting with the 1901 prize to Jacobus H. van't Hoff. The Nobel Prize in Chemistry
Slide5 : The Nobel Prize in Chemistry 1901 the discovery of the laws of chemical dynamics and osmotic pressure in solutions Jacobus Henricus van't Hoff
Slide6 : The Nobel Prize in Chemistry 1902 sugar and purine syntheses Hermann Emil Fischer
Slide7 : The Nobel Prize in Chemistry 1903 Svante August Arrhenius the advancement of chemistry by his electrolytic theory of dissociation
Slide8 : The Nobel Prize in Chemistry 2000 Alan J. Heeger, Alan G. MacDiarmid, Hideki Shirakawa the discovery and development of conductive polymers
Slide9 : The Nobel Prize in Chemistry 2001 William S. Knowles, Ryoji Noyori, K. Barry Sharpless chirally catalysed hydrogenation reactions & oxidation reaction
Slide10 : The Nobel Prize in Chemistry 2002 John B. Fenn, Koichi Tanaka, Kurt Wüthrich the development of methods for identification and structure analyses of biological macromolecules
Slide11 : The Nobel Prize in Chemistry 2003 Peter Agre, Roderick MacKinnon discoveries concerning channels in cell membranes (water channel & ion channel)
Slide12 : Who is the Nobel prize winner
in Chemistry, 2004? Aron Ciechanover, Avram Hershko, Irwin Rose
Slide13 : Aaron Ciechanover : Israel, Technion – Israel Institute of Technology Haifa
Avram Hershko : Israel, Technion – Israel Institute of Technology Haifa,
Irwin Rose : USA, University of California Irvine, CA “kiss of death”
the discovery of ubiquitin-mediated protein degradation
Slide14 : Breaking down of proteins:
~ Not so many researchers were interested.
~ Aaron Ciechanover, Avram Hershko and Irwin Rose
~ At the beginning of the 1980s, regulated protein degradation.
Naming : In 1975, Goldstein, a lymphocyte differentiation promoting factor, called ubiquitin as it was probably ubiquitous to living cells. Past: In the beggining
Slide15 : General information about
the ubiquitin
Slide16 : a small protein composed of 76 amino acids & found only in eukaryotic organism. Among eukaryotes, ubiquitin is highly conserved.
a heat-stable protein that folds up into a compact globular structure.
Involved in many cell processes (DNA repair, the regulation of transcription, and apoptosis)
encoded by a family of genes whose translation products are fusion proteins. What is the ubiquitin?
Slide17 : 3D Structure of ubiquitin
Slide18 : The ubiquitin genes
Slide19 : Ubiquitin Function
Slide20 : Short-lived proteins : typically key regulatory proteins & abnormal proteins.
long-lived proteins : the majority of proteins in the cell.
Balance b/w a protein’s degradation & synthesis →
dertermines the conc. of the protein in the cell.
Ubiquitin serves as a tag. It itself does not degrade proteins. The degradation is carried out by the 26S proteasome.
Slide21 : But…
Not accurate to think of Ub as a simple tag.
Ub’s degradation role may be to decrease the rate of dissociation b/w proteasomes & interacting substrate proteins.
Functions in an ATP-dependent fashion.
why is this? – because machinery is needed to specifically target the proteins that need to be degraded.
Slide22 : Ubiquitin’s biological functions
Slide23 : The Ubiquitin-Proteasome Pathway
Slide24 : Structure of the proteasome Model for the structure of the proteasome. Composite model of the 26S proteasome. The 20S proteasome core is shown in yellow; the 19S regulator (19S cap) structures are in blue. Voges,D., Zwickl,P. and Baumeister, W., 1999. The 26S proteasome: A molecular machine designed for controlled proteolysis. Annual Review of Biochemistry 68:1015-1068.)
Slide25 :
Slide26 : The ubiquitin-proteasome pathway If we were to mix ATP, ubiquitin, and an abnormal proteins…
Something else is needed to attach ubiquitin to such a proteins.
In most cases three tyepes of enzymes.
E1 : Ub-activation enzymes. Modify Ub so that it is in a reactive state.
E2 : Ub-conjugating enzymes. Actually catalyze the attachment of Ub to the substrate protein.
E3 : Ub-ligases. Usually function in concert w/ E2. Play a role in recognizing the substrate protein.
Ub is acivatied by E1 in an ATP-dep. fashion. E2 & E3 work together to recognize the protein and conjugate Ub to it.
Slide27 : Ubiquitin is attached to selected proteins via isopeptide bonds formed between the ubiquitin carboxy-terminus and free amino groups (a-NH2 terminus, Lys e-NH2 side chains) on the protein. Enzymatic reactions in the ligation of ubiquitin to proteins
Slide28 : The ubiquitin-proteasome degradation pathway.
Pink “lollipop” structures symbolize ubiquitin molecules. (Adapted from Figure 1 in Hilt,W., and Wolf, D.H., 1996. Proteasomes: Destruction as a program. Trends In Biochemical Sciences 21:96-102.)
Slide29 : Deubiquitination :
Another layer of complexity A class of enzymes that function to remove Ub from substrate proteins : rescuing them from degradation.
Ubiquitinated proteins could be deubiquinated prior to their association w/ the proteasome.
Represents means of regulating the concentration of proteins in a cell.
Slide30 : Diagram of the ubiquitin-proteasome degradation pathway
Slide31 : Degradation signals The N-degron, a correlation b/w the half-life of a protein & its N-terminal residue.
Ex) Ser : long lived w/ a half- life of more than 20 hrs.
Asp : only 3 mins.
Certain amino acid sequences.
Ex) PEST(enrinched w/ proline, glutamic acid, serine, threonine)
Other signals buried in the hydrophobic core.
Slide32 : Involvement of the ubiquitin system in diseases
Slide33 :
Slide34 : Involvement of the ubiquitin system in the pathogenesis of the diseases The pathological states can be divided into two groups
those that result from loss of function, a mutation in an enzyme or substrate that leads to stabilization of certain proteins.
those that result from a gain of function, resulting in accelerated degradation.
Slide35 : Cancer
결장암, 자궁암, 폐암, 유방암..
Cell cycle regulation
ex) CDKs(cycle-dependent kinases) & ubiquitin ligases.
Tumor suppressor proteins : p53 & human papilloma virus.
Slide36 : Genetic diseases
낭포성 섬유종(cystic fibrosis,CF) : The CF gene encodes the CF transmembrane regulator (CFTR), which is a chloride ion channel.
Angelman's syndrome : a rare inherited disorder characterized by mental retardation(정신지체), seizures(발작).
Liddle syndrome : an hereditary form of hypertension. Mutations affecting recognition of the channel, excessive reabsorption of sodium and water.
Slide37 : Immune & inflammatory responses
Transcription factor (NF-kB) : play essential roles in immune & inflammatory responses.
The virus-mediated destruction of the MHC molecules.
MHC molecules : important part of defence against virus infections.
Slide38 : Neurodegenerative diseases Alzheimer's (AD), Parkinson's and Lewy body diseases, amyotrophic lateral sclerosis (ALS) and Creutzfeld-Jakob disease (CJD).
알츠하이머 (Alzheimer's disease, AD) :
The most common cause of dementia. Excessive depostion of amyloid in the brain. Mainly characterized by the progressive and irreversible loss of neurons located in specific brain area.
Slide39 : Challenges for the future
Slide40 : The mechanism by which proteins are recognized.
The Idenfication fo degradation signals.
Research for medicines against various diseases.
: the proteasome inhibitor Velcade (PS341) The ubiquintin systems has become an interesting area of research