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Ubiquitination: The Garbage Cycle of a Cell
Grafton High School SMART Team: Dan Burgardt, Lexi Chopp, Ashley Emery, Alyssa Fletcher, Kaleigh
Kozak, Adam Schaenzer, Dustin Studelska, Lindsay Wendtlandt, Lindsay Zadra
Teacher: Fran Grant
Mentor: Namitha Vishveshwara, University of Illinois at Chicago
Ubiquitin-Proteasome System
Abstract
Within every cell, there exists a system known as the ubiquitin-proteasome system (UPS) that eliminates
damaged, misfolded or excess proteins. Unwanted proteins are tagged with ubiquitin, a small protein
that identifies other proteins as being ready for degradation. The process of activating and transferring
the ubiquitin to the protein is referred to as ubiquitination. Three proteins involved in this process are
the ubiquitin activating enzyme (E1), the ubiquitin conjugating enzyme (E2), and the ubiquitin ligase (E3).
Ubiquitination begins with ubiquitin being activated by and attaching to E1. E1 transfers ubiquitin to E2.
Then E2 delivers ubiquitin to the unwanted protein, either directly or through E3. Finally, the tagged
protein is broken down by the proteasome, which is the cell’s protein-degrading complex. E2 plays a
critical role in the ubiquitination process. Ubch5b is one of many E2s that is involved in tagging
unwanted proteins with ubiquitin. Researchers are studying the relationship between the yeast Ubch5b
and a specific form of misfolded protein called prions. Prions are unique because when one protein
takes the prion form, correctly folded proteins also misfold into prions and aggregate. Prions are
infectious proteins; they are not viral or bacterial. Mad cow disease is caused by the presence of prions.
In yeast, when Ubch5b is deleted, it leads to increased prion formation. The exact role of the yeast
Ubch5b in increased yeast prion formation is still unknown.
E2
E1 activates
ubiquitin
E3 E2
E2 passes
ubiquitin
on to E3
Activated
ubiquitin is
transported by
E2
E3 E2
Misfolded
protein
Got Mad Cow?
Bovine Spongiform Encephalopathy (BSE), also referred to as "Mad
Cow Disease“, is an illness that attacks the brain and spinal cord. The
name "Mad Cow Disease" comes from the strange behaviors, including
aggression and lack of coordination, that are associated with infected
cattle. BSE is the result of prion infection within the brain.
Ubiquitin is
recycled
Take Out the Trash!
The Ubiquitin-Proteasome system (UPS) is
how the cell rids itself of unwanted,
unassembled, or damaged proteins.
E3 attaches
ubiquitin “tag” to
misfolded protein
A cow displaying symtoms of Bovine Spongiform Encephalopathy
Proteasome
Prion Formation
Occasionally
Normally folded
form
Misfolded prion
form
Tagged protein
heads for
proteasome
Proteasome
disassembles
misfolded protein
Efficiently
Normally folded form
induced into the prion form
Prion aggregate
A prion is a unique, misfolded form of a normal protein. As illustrated in the
diagram above, the prion form initiates a chain reaction by causing other normal
proteins of the same type to mis-fold and aggregate together. Though misfolded
proteins are targeted to the ubiquitin system (shown in the diagram to the right),
the prion escapes this targeting, causing these prion misfolds to accumulate in
the cell. Prions are not only present in mammalian cells, but also in yeast cells
which has made prion research easier.
A SMART Team project supported by the National Institutes of Health (NIH) – National Center for
Research Resources Science Education Partnership Award (NCRR-SEPA)
What is the connection between the UPS and prions?
Ubch5b (in yeast)
E2
Increase
Normally folded form
Prion form
In yeast, when Ubch5b(E2) is removed from the ubiqination process, an increase in
prion formation has been observed. The easiest explanation would be that a
decrease in E2 leads to an increase in misfolded protein, which might lead to
increased prion formation. However, as the protein is not normally seen to associate
with ubiquitin, the effect of deletion of Ubch5b is probably mediated indirectly.