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Get Hooked: Cross-ßeta Structure Leads to
Domino Effect in Prion Disease
St. Joan Antida SMART Team Authors: Chalhoub , J. Dargis, C. Dornfeld, C. Garcia, E. Teacher: Ms. Anne Staab
Mentor: Dr. Anita Manogaran, University of Illinois- Chicago
Abstract
In the study of protein function, one of the most important factors to
the outcome of a molecule is the way it folds. If a protein does not fold
properly, it will be unable to meet its function. The cells in our body contain
ways to correct or rid our body of these misfolded proteins. In some cases,
when a protein misfolds, it can aggregate and/or form fibers to create a
prion, which then can induce other proteins to misfold and aggregate.
Baker’s yeast has been known to have a number of prions in cluding [PSI+],
which is the prion form of the Sup35 protein. The Sup35 protein is
important in translational termination, but when in the prion form, it loses
the ability to efficiently perform this process. Within prion domain of Sup35,
located in the N-terminus, a seven amino acid region, GNNQQNY, has
been found to form a “cross-beta spine” structure, which is thought to
contribute to the fibrillar structure of the prion. The researchers at
University of Illinois-Chicago's Laboratory for Molecular Biology are
interested in the structure of GNNQQNY because it helps in understanding
the structural change of Sup35 from a normal form to the prion form.
Furthermore, it can provide insight to how prions fold in human/mammalian
systems.
Prion Sup35 [PSI] +
Our Model
? Structure of the Sup35 Prion we have modeled: GNNQQNY
? It is located in the cytoplasm
? What does it do normally?
o Sup35 in yeast participates in making other proteins in the cell
? 20% of all misfolded proteins are not corrected; some do not cause
problems while others cause brain diseases
? [PSI]+ is the misfolded infectious prion form of Sup35
? The molecule begins to misfold at the N -terminus of Sup35
? The C -terminus does not change
? These seven amino acids form interlocking beta sheet-like structures
Our model is a physical depiction of the [PSI]+ prion of
Sup35. This specific protein is uneventful on its own, but
once it misfolds, it can cause major dise ases such as Mad
Cow Disease or Scrapie . Our model was first created on the
RP RASMOL computer program and then physically formed
at MSOE’s Rapid Prototyping Center.
? Wet interface amino acids: Asparagines 2 and 6;
Glutamine 4
o inner “linking” atoms
? Dry interface amino acids: Glycine 1; Asparagine
3; Glutamine 5; Tyrosine 7
o Located on the outer part of the model
? Backbone: Light Grey
? N-terminus is indicated with a blue atom
? Glycine 1 was missing a hydrogen in the PDB file
and is therefore not colored
? Asparagine 2 and 6 are colored magenta
? Asparagine 3 is colored violet
? Glutamine 4 is a bright green
? Glutamine 5 is a darker green
? Tyrosine 7 is colored a dark red
? –COOH terminus is indicated with red atoms.
Process of Protein Misfolding
What is a Prion?
? An infectious particle made of protein
? A misfolded protein consisting of a cross-beta sheet, which
causes a fib rillar form
? Fibrillar fibers cause the proteins not to function
? Three methods of prion infection:
o Inherited: part of your genes ie. Creutzfeld -Jakob Disease
o Acquired: eating infected beef ie. Mad Cow Disease
o Sporadic: when misfolded proteins are not repaired by the
cell and recruit other proteins
+
+
(Nature)
Structure of GNNQQNY from yeast Prion
Sup35
A normal protein misfolds to prion state and is added to another normal protein. As
more normal proteins are added they begin to misfold.
Comparison of Normal Sup35 Protein vs. Misfolded Protein
Alterations in Brain Tissue Caused by Prions
Normal Protein
Misfolded Protein
Conclusion
Prion Diseases
(Manogaran)
The first image is a normal Sup35 expressed in the cytoplasm. The
second is an aggregated prion that appears as dots.
Why Do We Study Yeast?
? Yeast prion misfolding is very similar to human protein misfolding
? Research is safer because the risk of human infection is lessened
? Human form of disease is contagious to study even after the autoclaving
process
? Yeast makes it possible for the whole process of the disease’s
misfolding to be studied
? In humans we can not study the beginning of the process because it can
only be studied once the patient is dead
The most important reason for this research is that the
understanding of the process of prion disease is essential to
discovering a cure. Our model shows the sequence and structure
of the GNNQQNY section of the prion, which may signal the prion
and other normal proteins to misfold. This model may help
scientists decide the best approach to finding possible cures for
prion diseases. The similarities between prion disease and
Alzheimer’s found in recent research may help scientists discover
cures for both disorders.
The prion diseases in mammalian species are:
? Scrapie (sheep): acquired
? Transmissible mink encephalopathy (mink): acquired
? Chronic wasting disease (deer, elk): acquired
? Bovine spongiform encephalopathy (cows): acquired
Prion diseases in humans are:
? Creutzfeld-Jakob disease: inherited
? Gerstmann-Straussler -Scheinker syndrome: inherited
? Fatal familial insomnia: inherited
? Kuru: acquired and inherited
? Alpers: inherited
(DeArmond)
Images and Information Courtesy of:
Anita Manogaran , University of Illinois - Chicago
Microbiology @ Leicester Website . http://www.micro.msb.le.ac.uk/
3035/prions.html.
Nelson, Rebecca and Liebman , Susan W. et al. Nature Journal Vol. 435/9
(June 2005) and Vol. 12 (July 2005)
Stephen J. DeArmond , M.D., Ph. D., Professor of Pathology
(Neuropathology), Department of Pathology, Univ ersity of
California San Francisco