Discovery and Characterization of Chaperone-Independent Substrates of the CHIP Ubiquitin Ligase- [electronic resource]
Discovery and Characterization of Chaperone-Independent Substrates of the CHIP Ubiquitin Ligase- [electronic resource]
- Material Type
- 단행본
- 0016934851
- Date and Time of Latest Transaction
- 20240214101702
- ISBN
- 9798380334655
- DDC
- 574
- Author
- Callahan, Matthew.
- Title/Author
- Discovery and Characterization of Chaperone-Independent Substrates of the CHIP Ubiquitin Ligase - [electronic resource]
- Publish Info
- [S.l.]: : University of California, San Francisco., 2023
- Publish Info
- Ann Arbor : : ProQuest Dissertations & Theses,, 2023
- Material Info
- 1 online resource(91 p.)
- General Note
- Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
- General Note
- Includes supplementary digital materials.
- General Note
- Advisor: Gestwicki, Jason.
- 학위논문주기
- Thesis (Ph.D.)--University of California, San Francisco, 2023.
- Restrictions on Access Note
- This item must not be sold to any third party vendors.
- Abstracts/Etc
- 요약Protein turnover through endolysosomal degradation and the ubiquitin proteasome system are critical for maintaining protein homeostasis. These pathways protect the cell from accumulation of misfolded proteins, coordinate critical signaling processes, and facilitate recycling pathways that are central to cellular health. An integral member of these systems is the E3 ubiquitin ligase CHIP, which facilitates the turnover of damaged or terminally misfolded proteins. Canonically, substrate recognition by CHIP is dependent on Hsp70 or Hsp90 chaperones, which serve as intermediaries between a misfolded client and CHIP. However, emerging evidence suggests that CHIP also has the capacity to recognize substrates independent of a chaperone binding partner. In this dissertation, we explore the biological relevance of such chaperone-independent substrates by exploring interactions predicted by a biophysical scoring function we previously developed, termed CHIPscore.In the first chapter, I and others describe one such interaction between CHIP and the relatively uncharacterized, membrane-anchored protein CHIC2. We find that CHIC2 binding strongly attenuates CHIP activity, and that CHIC2 knockout phenocopies CHIP knockout in certain cell types, implying that chaperone-independent interactions can sometimes predominate CHIP's biological functions. Furthermore, loss of the CHIP-CHIC2 interaction induces neurodegeneration and shortens lifespan in C. elegans, demonstrating that formation of this chaperone-independent complex is important in animals. We propose that CHIC2 attenuates CHIP activity at the membrane, offering a novel mechanism by which this ubiquitin ligase can be regulated.In the second chapter, I explore additional chaperone-independent interactors beyond CHIC2 that are predicted by CHIPscore. In preliminary results, I demonstrate interactions between CHIP and three additional proteins. These proteins are completely uncharacterized and reside at different subcellular localizations, suggesting that CHIP may be regulated at various locations within the cell through mechanisms that are not yet understood. This work opens substantial new avenues upon which future studies should be based.
- Subject Added Entry-Topical Term
- Biochemistry.
- Subject Added Entry-Topical Term
- Chemistry.
- Subject Added Entry-Topical Term
- Cellular biology.
- Subject Added Entry-Topical Term
- Neurosciences.
- Index Term-Uncontrolled
- Chaperone
- Index Term-Uncontrolled
- Ubiquitin proteasome system
- Index Term-Uncontrolled
- Proteomics
- Index Term-Uncontrolled
- Misfolded proteins
- Index Term-Uncontrolled
- Neurodegeneration
- Added Entry-Corporate Name
- University of California, San Francisco Chemistry and Chemical Biology
- Host Item Entry
- Dissertations Abstracts International. 85-03B.
- Host Item Entry
- Dissertation Abstract International
- Electronic Location and Access
- 로그인 후 원문을 볼 수 있습니다.
- 소장사항
-
202402 2024
Detail Info.
- Reservation
- Not Exist
- My Folder
- First Request
- 비도서대출신청
- 야간 도서대출신청
로그인 후 이용 가능합니다.