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Protein biogenesis and degradation. MBB443/743. Prof. Michel R. Leroux. Fall semester 2012. Wednesday & Friday 8:30 am – 10:20 am. SECB 1012. Office hours. Office South Sciences Bldg, SSB6144. Telephone 778-782-6683. e-mail [email protected]

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protein biogenesis and degradation
Protein biogenesis and degradation

MBB443/743

Prof. Michel R. Leroux

Fall semester 2012

Wednesday & Friday 8:30 am – 10:20 am

SECB 1012

office hours
Office hours

Office

South Sciences Bldg, SSB6144

Telephone

778-782-6683

e-mail

[email protected]

• I will be available after the lectures in class or in my office (Wednesday and Friday)

• if you have questions, please try to see me right after class

• any e-mails to me should have the header “MBB443”

course outline
Course outline

- lecture

- student presentation(s)

Wednesdays

& Fridays

- no specific tutorial time(s) assigned- no required text

• total # classes scheduled: 26

• class presentations: - students give 1-2 oral presentations

(in pairs if too many students)

- 20 minutes each

- thepaper(s) will be assigned

• 1 term paper (in pairs if too many students)

• 2 exams

class presentations
Class presentations

2. introduce paper, giving enough background information for everyone to understand the paper; this should include some background information not found in the paper itself- also explain the research goals

~5 min

3. present key experimental data along with brief explanations of procedures; the data presented can be a subset of all of the paper’s data

4. explain the results obtained

~15 min

Powerpoint presentations: on my computer

assigned at least one week in advance

Guidelines:

1. prepare a 1-page (maximum) summary of the presentation that is distributed to the class(please e-mail for distribution)

If time permits: class discussion- approaches used were appropriate? - results were convincing? - further studies required?

term paper
Term paper

based on NSERC grant application

Content

• topic should be related to course material

• Introduction; requires literature search (~4 double-spaced pages)

• research proposal and references (~6 double-spaced pages)

• research proposal should describe a study that would advance our knowledge of biogenesis and/or degradation {or related topic}

- describe goal, importance, procedures (brief), alternate experiments, interpretation of (anticipated) results, conclusions

Format of manuscript

• 10 double-spaced pages, including references

• 2-2.5 cm margins all around

• 12 pt Times New Roman font

• references should be numbered and have the following style:

Deere, J., McIntosh, A. and Crusher, W. (2000) Studies on the refolding of Ribonuclease A. Nature38, 345-368.

Important !

• you must use your own words when writing the paper; in the rare case you need to use someone’s wording, use quotations and reference the paper

Timeline• wait about one month before choosing your topic; report due November 16

exams
Exams

There are two exams

• anything mentioned in class is fair game:

- lectures

- assigned papers (~1 for each term)

- class presentations (no detailed questions)

- in-class discussions

• answering exam questions may also require reading a small portion of a real scientific publication

• mostly short, written answers (a word, a sentence or a paragraph)

• focus is on understanding, not memorization; I will tell you if there is something you should specifically memorize.

• no final exam scheduled

Finished on last day of class (Nov. 30) !

lectures info available on my web site
Lectures, info available on my web site

www.sfu.ca/~leroux

click on teaching and download lectures and other stuff (e.g. research proposal info)

lowercase PASSWORD for some files: mbb-sfu

grading
Grading

(or 40%)

(or 25%)

central dogma of biology
Central dogma of biology

folding,

assembly,

targeting

cellular

proteins

degradation (turnover)

FUNCTIONAL

(NATIVE)

PROTEIN

amino acids,

peptides

cellular

proteins

cellular

proteins

regulation of conformation/

function

transcription

translation

DNA

RNA

PROTEIN

replication

link between biogenesis and degradation non native proteins
Link between biogenesis and degradation: ‘non-native’ proteins

both processes can be grouped under the heading of quality control.

Non-native (unfolded, misfolded, denatured) protein:

a protein that is not properly folded and is not in a functional state

• biogenesis signifies the ‘birth’ of proteins, or the transition between non-native to native states

- biogenesis includes: folding, assembly, transport to and across biological membranes, refolding, chemical or structural modification

• degradation represents the ‘death’ of proteins, or the transition from native to ‘non-native’ states to basic constituents

- degradation includes the disposal of damaged (non-native) proteins and the timely, regulated turnover of various cellular proteins

cellular processes involving non native proteins folding and assembly
Cellular processes involvingnon-native proteins: folding and assembly

• proteins are synthesized on the ribosome and must fold/assemble to become native

- proteins are synthesized as unfolded polypeptide chains

- folding occurs co-translationally

- folding (and assembly) to the

native state requires the complete

polypeptide chain

folding

assembly

cellular processes involving non native proteins refolding
Cellular processes involvingnon-native proteins: refolding

various cellular

proteins

cellular stress

heat/cold

Native

protein

non-native

(unfolded)

protein

proteotoxic

chemicals

aggregated

protein

intracellular

changes

cellular processes involving non native proteins transport
Cellular processes involvingnon-native proteins: transport

• protein transport to, and across biological membranes

- protein must be maintained

in a translocation-competent

state

- protein must not misfold or

aggregate

- protein must be directed to

proper membrane / cellular

compartment

• also: intracellular transport (to specific locations in the cytosol, nucleus, etc. (but this typically involves native proteins)

cellular processes involving non native proteins regulation of protein conformation function
Cellular processes involvingnon-native proteins: regulation of protein conformation/function

• under certain circumstances, the conformation

(activity) of some proteins must be modulated

- heat shock transcription factor is activated only during a cellular stress

- steroid receptors must be kept in a form that is competent to bind ligand, but is not active

- signalling molecules (kinases) are kept in an inactive conformation until phosphorylated

inactive,

non-

native

cellular

event

active,

native

cellular processes involving non native proteins degradation
Cellular processes involvingnon-native proteins: degradation

unfolding

proteolysis

proteolysis

*

*

*

amino

acids

peptides

Protein destined

for degradation

antigen

presentation

*

steps involve various

cellular machineries

cellular processes involving non native proteins quality control
Cellular processes involvingnon-native proteins: quality control

non-native

protein

unfolding

refolding

refolding

degradation

Native

protein

peptides,

amino

acids

Native

protein

protein degradation cellular roles
Protein degradation: cellular roles

Degradation involves numerous cellular processes, including:

processing of nascent polypeptides

cleavage of proteins to peptides for antigen presentation

destruction of proteins that are inefficiently folded/processed

degradation of aberrant (mutant) proteins

turnover of cell-cycle or other proteins that are short-lived or whose presence in the cell is strictly regulated

destruction of proteins damaged due to cellular stresses (oxygen radicals, elevated/reduced temperatures, etc.)

turnover of proteins that have lost activity over time

- there are a large variety of proteases in the cell, and degradation is strictly controlled

protein misfolding disease amyloidosis
Protein misfolding disease: amyloidosis

• at least

16 different

proteins are

implicated in

amyloid

diseases

• a number of

different proteins

can be induced

to form fibrils

in vitro as well

amyloid formation

amyloid structure
Amyloid structure

electron microscopy

model of filament

cross-section

Courtesy of Helen Saibil

Dept. of Crystallography, Birkbeck College London

protein modification
Protein modification

Ubiquitination Lys degradation/other

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