Vascular K
| Autor: | Min Woo, Sung, Zhongying, Yang, Camden M, Driggers, Bruce L, Patton, Barmak, Mostofian, John D, Russo, Daniel M, Zuckerman, Show-Ling, Shyng |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Cantú syndrome
endocrine system Kir6.1 Potassium Channels Hypertrichosis Cardiomegaly Muscle Smooth Biological Sciences Osteochondrodysplasias Sulfonylurea Receptors Biochemistry Adenosine Diphosphate sulfonylurea receptor 2B Structure-Activity Relationship Adenosine Triphosphate KATP Channels ATP-sensitive potassium channel Humans ABC transporter Potassium Channels Inwardly Rectifying Pancreas |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance Vascular KATP channels formed by the potassium channel Kir6.1 and its regulatory protein SUR2B maintain blood pressure in the physiological range. Overactivity of the channel due to genetic mutations in either Kir6.1 or SUR2B causes severe cardiovascular pathologies known as Cantú syndrome. The cryogenic electron microscopy structures of the vascular KATP channel reported here show multiple, dynamically related conformations of the regulatory subunit SUR2B. Molecular dynamics simulations reveal the negatively charged ED-domain in SUR2B, a stretch of 15 glutamate (E) and aspartate (D) residues not previously resolved, play a key MgADP-dependent role in mediating interactions at the interface between the SUR2B and Kir6.1 subunits. Our findings provide a mechanistic understanding of how channel activity is regulated by intracellular MgADP. Vascular tone is dependent on smooth muscle KATP channels comprising pore-forming Kir6.1 and regulatory SUR2B subunits, in which mutations cause Cantú syndrome. Unique among KATP isoforms, they lack spontaneous activity and require Mg-nucleotides for activation. Structural mechanisms underlying these properties are unknown. Here, we determined cryogenic electron microscopy structures of vascular KATP channels bound to inhibitory ATP and glibenclamide, which differ informatively from similarly determined pancreatic KATP channel isoform (Kir6.2/SUR1). Unlike SUR1, SUR2B subunits adopt distinct rotational “propeller” and “quatrefoil” geometries surrounding their Kir6.1 core. The glutamate/aspartate-rich linker connecting the two halves of the SUR-ABC core is observed in a quatrefoil-like conformation. Molecular dynamics simulations reveal MgADP-dependent dynamic tripartite interactions between this linker, SUR2B, and Kir6.1. The structures captured implicate a progression of intermediate states between MgADP-free inactivated, and MgADP-bound activated conformations wherein the glutamate/aspartate-rich linker participates as mobile autoinhibitory domain, suggesting a conformational pathway toward KATP channel activation. |
| Databáze: | OpenAIRE |
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