Molecular Biophysics I
2005
Session #2
Protein Conformation:
Folding versus Polymerization
February 02, 2005
BioMed 155-2
1:00 p.m. - 3:50 p.m.
In recent years it has become apparent that many human diseases are
characterized by the appearance of 'plaques' or other deposits containing
aggregated proteins. While the formation of these aggregates is still not
understood in detail, current evidence suggests they originate via 'ordered',
rather than random, interactions between polypeptides. In fact, Christopher
Dobson has characterized such interactions involving biological polypeptides
(i.e., proteins) as forming a "primordial" structure, to differentiate that
conformation from the conformations we generally describe as arising from
protein "folding".
Thus, in this session, we explore the concept of two different conformations of proteins, some of the factors thought to influence the partitioning of proteins between the two conformations, and finally a brief overview of the diseases characterized by protein aggregates.
Since we have not yet formed groups, the reference material listed below has been apportioned among students according to the numbers associated with each student as shown on the class roster (open PDF file using same password as used with the course page on eReserves).
General suggestions: The assigned papers for the most part are descriptive, and contain lots of information. Thus, you should attempt to convey an overall summary of the paper, and then identify what you consider the main points.
Notice that two of the papers (Refs # 6 & 9) have not been assigned to specific students; all students should look at both papers, and we'll go over each in class. Except for reference #4, all papers should be available electronically using the UAMS Library's online catalog. (Reference #4 has been posted to the course page in the eReserves.)
1. Dobson, C.M.
Protein-misfolding diseases: Getting out of shape. Nature, 418:
729-730, 2002.
Student #10
2. Dobson, C.M.
PROTEIN CHEMISTRY: In the Footsteps of Alchemists. Science, 304:
1259-1262, 2004.
Student #9
3. Sipe, J.D. and
Cohen, A.S. Review: History of the amyloid fibril. Journal of Structural
Biology, 130: 88-98, 2000.
Student #8
[1]4.
Westermark, P., Benson, M.D., Buxbaum, J.N., Cohen, A.S., Frangione, B.,
Ikeda, S., Masters, C.L., Merlini, G., Saraiva, M.J., and Sipe, J.D. Amyloid
fibril protein nomenclature - 2002. Amyloid, 9: 197-200, 2002.
Student #7
5. Fandrich, M.,
Fletcher, M.A., and Dobson, C.M. Amyloid fibrils from muscle myoglobin -
Even an ordinary globular protein can assume a rogue guise if conditions are
right. Nature, 410: 165-166, 2001.
Student #6
6. Fandrich, M. and Dobson, C.M. The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation. EMBO J., 21: 5682-5690, 2002.
7. Hou, L. and
Zagorski, M. Sorting out the driving forces for parallel and antiparallel
alignment in the A-beta peptide fibril structure. Biophys.J., 86:
1-2, 2004.
Student #5
8. Gazit, E. A
possible role for pi-stacking in the self-assembly of amyloid fibrils.
FASEB J., 16: 77-83, 2002.
Student #4
9. Temussi, P.A., Masino, L., and Pastore, A. From Alzheimer to Huntington: why is a structural understanding so difficult? EMBO J., 22: 355-361, 2003.
10. Gazit, E. The
"Correctly Folded" state of proteins: is it a metastable state? Angewandte
Chemie, International Ed. in English. 41: 257-259, 2002.
Student #3
11.
Richardson, J.S. and Richardson, D.C. Natural beta-sheet proteins use
negative design to avoid edge-to-edge aggregation. Proc.Natl.Acad.Sci.USA,
99: 2754-2759, 2002.
Students #1 & 2
[Note: This paper is complicated by the use of lots of jargon,
acronyms, and structural descriptors. Try to get past these barriers to
glean the overall message of the paper, using only a few examples to
illustrate. You need not collaborate; actually, two different viewpoints
should be useful during the discussion of this paper.]