The Role of Intracellular Domains in KCNH Potassium Channel Gating
Başlık:
The Role of Intracellular Domains in KCNH Potassium Channel Gating
Yazar:
Zhao, Yaxian, author.
ISBN:
9780438029859
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (153 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Gail A. Robtertson Committee members: Baron Chanda; Cynthia Czajkowski; Barry Ganetzky; Mathew V. Jones; Gail A. Robertson.
Özet:
KCNH channels are voltage-gated potassium channels that are characterized by their highly conserved N-terminal PAS domain and C-terminal cyclic-nucleotide binding homology domain (CNBhD), which forms a complex with the PAS domain. Proper function of KCNH channels is important for a series of important physiological processes such as regulating duration of cardiac action potential and maintaining normal neuronal membrane excitability. The X-ray crystal structure of mouse EAG1 channel, the founding member of KCNH family, demonstrates that the CNBhD represents an "intrincally -liganded" state. Interestingly, mutations or deletions of the CNBhD or an N-terminal Per-Arnt-Sim (PAS) domain cause dramatic alterations of gating. The two domains form a complex whose interface is replete with disease-associated mutations. Although a high-resolution X-ray crystal structure of the PAS-CNBhD complex has been described, the functional ramifications for mutant defects at the interface are not well understood. In this thesis, I focused on understanding the regulatory roles of intracellular domains, N- terminal PAS domain and C-terminal CNBhD domain, on human EAG1 channel gating. Using electrophysiological method, I demonstrated that mutating the intrinsic ligand of hEAG1 channel to different amino acids created distinct CNBhD conformations that can communicate to the gating machinery. I also found that the C-terminus is required for the PAS domain to regulate the channel and that the intrinsic ligand is important in stabilizing the PAS-CNBhD complex. Overall, this thesis elucidates the functional impact of the intrinsic ligand on EAG1 gating, identifies the intrinsic ligand as a molecular determinant of the PAS domain and CNBhD interaction. The knowledge gained in this thesis provides new insight into the gating and regulation mechanisms of KCNH channels.
Notlar:
School code: 0262
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678033.1) | 678033-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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