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Identification of a Multisubunit E3 Ubiquitin Ligase Required for Heterotrimeric G-Protein Beta-Subunit Ubiquitination and cAMP Signaling
Başlık:
Identification of a Multisubunit E3 Ubiquitin Ligase Required for Heterotrimeric G-Protein Beta-Subunit Ubiquitination and cAMP Signaling
Yazar:
Young, Brian Daniel, author.
ISBN:
9780438019720
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (117 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: James A. Wohlschlegel Committee members: Hilary Coller; Peter Tontonoz; Jorge Torres.
Özet:
GPCRs are stimulated by extracellular ligands and initiate a range of intracellular signaling events through heterotrimeric G-proteins. Upon activation, G-protein alpha-subunits (Galpha) and the stable betagamma-subunit dimer (Gbetagamma) bind and alter the activity of diverse effectors. These signaling events are fundamental and subject to multiple layers of regulation. In this study, we used an unbiased proteomic mass spectrometry approach to uncover novel regulators of Gbetagamma. We identified a subfamily of potassium channel tetramerization domain (KCTD) proteins that specifically bind Gbetagamma. Several KCTD proteins are substrate adaptor proteins for CUL3--RING E3 ubiquitin ligases. Our studies revealed that a KCTD2-KCTD5 hetero-oligomer associates with CUL3 through KCTD5 subunits and recruits Gbetagamma through both subunits. Using in vitro ubiquitination reactions, we demonstrated that these KCTD proteins promote monoubiquitination of lysine-23 within Gbeta1/2. This ubiquitin modification of Gbeta 1/2 is also observed in human cells and is dependent on these substrate adaptor proteins. Because these KCTD proteins bind Gbetagamma in response to G-protein activation, we investigated their role in GPCR signaling. Their deletion strongly impairs cAMP generation and downstream signaling pathways in response to signaling activation. Consistent with these results, depletion of CUL3, the component of the E3 ligase that binds KCTD proteins, causes similar defects. Together, our studies suggest that a KCTD2/KCTD5--CUL3--RING E3 ubiquitin ligase recruits Gbetagamma in response to signaling, monoubiquitinates lysine-23 within Gbeta, and stimulates adenylyl cyclases---Gbetagamma effectors---to positively regulate cAMP signaling.
Notlar:
School code: 0031
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(682435.1) | 682435-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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