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THE HONG KONG UNIVERSITY OF SCIENCE AND TECHNOLOGY
Nano Science and Technology Program
MPhil Thesis Presentation
Molecular Interaction of PICKI and ATXN3
by
Ho Chun LAI
SCA3 is one of the nine known polyQ diseases which would be inherited in an autosomal dominantly. Exact
disease mechanism of SCA3 is not fully understood and there is currently no known therapy to affect disease
progression. SCA3 is solely caused by CAG expansion of ATXN3, a deubiquitinase with a unique
deubiquitinating mechanism. ATXN3 was screened as an interactor of PICK1 through yeast-two hybrid, an
adaptor protein with important functions in protein trafficking inside the central nervous system and other
various organs. PICK1 was found to mediate neurodegeneration of SCA3 as well as other neurodegenerative
diseases through an unknown pathway in a Drosophila model. Yet no researches were done to investigate
further on the interaction of PICK1 with ATXN3 in a mammalian system.
In my study, PICK1 was verified to interact with ATXN3 in vitro and both PICK1 and ATXN3 bind to
each other with multiple sites. Although the deubiquitinase domain of ATXN3 binds to PICK1, ATXN3 does
not deubiquitinate PICK1 in vitro. Further mapping showed that BAR domain of PICK1 binds specifically to
the unstructured C-terminus of ATXN3, where the polyQ tract resides. Such binding is specific to the BAR
domain of PICK1 but not BAR domains of other proteins identified with sequence homology. On top of the
specific interaction, the BAR domain of PICK1 recruits the Qtract from cytosol to form clusters. In addition,
two distinct forms of nuclear inclusion bodies are found in the SCA3 model mice brain, along with additional
brain areas containing nuclear inclusion bodies were identified. Further studies on the interaction of these two
proteins may reveal pathological mechanism of SCA3 and identify new drug target.
Date:
August 10, 2015 (Monday)
Time: 10:00am
Venue: Room 2503, Academic Building
HKUST (via Lifts 25-26)
All interested are welcome!