Structural Studies of the Proteasome activator BLM10

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Publication Type dissertation
School or College School of Medicine
Department Biochemistry
Author Sadre-Bazzaz, Kianoush
Title Structural Studies of the Proteasome activator BLM10
Date 2010-02-08
Description The 20S proteasome is an intracellular protease found in all kingdoms of life. In eukaryotes, the ubiquitin-proteasome is a major proteolytic pathway involved in the turn-over of cytosolic and nuclear proteins and controls many cellular processes. The 20S recruits one of three classes of proteasome activators that modulate and enforces its function: the PA700, the PA28 and the PA200/Blml0 families. In contrast to PA700 and PA28 that function by binding to the 20S as oligomeric structures, PA200/Blml0 binds to the 20S as a single polypeptide chain of about 250kDa. This dissertation focuses on structural studies of the BlmlO proteasome activator from the budding yeast S. cerevisiae. The 18A cryo-EM reconstruction of Blml0:20S complex shows that BlmlO is a dome-shaped protein that binds to the ends of the proteasome and opens its gate. The similarity of the cryo-EM structures of BlmlO and its bovine homologue, PA200, suggested a similar biological function; however, the precise biological role of PA200/Blml0 remains to be determined. To further advance understanding of BlmlO function, we determined the crystal structure of Blml0:20S complex at 3.4A resolution. BlmlO is a HEAT-repeat containing protein that folds into a left-handed solenoid burying a large solvent cavity over the 20S a subunits. BlmlO contains a pore large enough to allow passage of small peptides explaining the biochemical activity of Blml0:20S complex. Binding to the 20S occurs through many loops from different HEAT repeats and also by BlmlO's single C-terminal carboxylate that forms a salt bridge with a conserved lysine of 20S. Intriguingly, the penultimate residue of BlmlO is a conserved tyrosine that opens the gate locally at the proline reverse turn of a-5. This repositioning at a-5 is propagated to the neighboring subunits: a-6, 7, and 1 triggering their open conformation while disordering the gate at a-2, 3, and 4. Though the partial disordering of the 20S gate seems to be unique to BlmlO, the penultimate tyrosine of BlmlO is shared by subunits of the PA700 activator and provides a model for proteasome activation by ATPase activators.
Type Text
Publisher University of Utah
Subject Proteolytic Enzymes
Subject MESH Peptide Hydrolases
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Structural studies of the proteasome activator BLM10." Spencer S. Eccles Health Sciences Library. Print version of "Structural studies of the proteosome activator BLM10. available at J. Willard Marriott Library Special Collection. QP6.6 2009.S23.
Rights Management © Kianoush Sadre-Bazzaz
Format Medium application/pdf
Format Extent 3,395,787 bytes
Source Original: University of Utah Spencer S. Eccles Health Sciences Library
Conversion Specifications Original scanned on Fujitsu fi-5220G as 400 dpi to pdf using ABBYY FineReader 10
ARK ark:/87278/s6ng558s
Setname ir_etd
Date Created 2012-04-23
Date Modified 2012-04-23
ID 193680
Reference URL https://collections.lib.utah.edu/ark:/87278/s6ng558s
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