Source:http://linkedlifedata.com/resource/pubmed/id/19221509
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
1
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| pubmed:dateCreated |
2009-3-11
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| pubmed:abstractText |
The renal inward rectifying potassium channel Kir1.1 plays key roles in regulating electrolyte homeostasis and blood pressure. Loss-of-function mutations in the channel cause a life-threatening salt and water balance disorder in infants called antenatal Bartter syndrome (ABS). Of more than 30 ABS mutations identified, approximately half are located in the intracellular domain of the channel. The mechanisms underlying channel dysfunction for most of these mutations are unknown. By mapping intracellular mutations onto an atomic model of Kir1.1, we found that several of these are localized to a phylogenetically ancient immunoglobulin (Ig)-like domain (IgLD) that has not been characterized previously, prompting us to examine this structure in detail. The IgLD is assembled from two beta-pleated sheets packed face-to-face, creating a beta-sheet interface or core, populated by highly conserved side chains. Thermodynamic calculations on computationally mutated channels suggest that IgLD core residues are among the most important residues for determining cytoplasmic domain stability. Consistent with this notion, we show that two ABS mutations (A198T and Y314C) located within the IgLD core impair channel biosynthesis and trafficking in mammalian cells. A fraction of core mutant channels reach the cell surface, but are electrically silent due to closure of the helix-bundle gate. Compensatory mutation-induced rescue of channel function revealed that IgLD core mutants fail to rectify. Our study sheds new light on the pathogenesis of ABS and establishes the IgLD as an essential structure within the Kir channel family.
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| pubmed:grant | |
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:issn |
1933-6969
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
3
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
57-68
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:19221509-Amino Acid Sequence,
pubmed-meshheading:19221509-Animals,
pubmed-meshheading:19221509-Cell Line,
pubmed-meshheading:19221509-Computer Simulation,
pubmed-meshheading:19221509-Hot Temperature,
pubmed-meshheading:19221509-Humans,
pubmed-meshheading:19221509-Hydrophobic and Hydrophilic Interactions,
pubmed-meshheading:19221509-Immunoglobulins,
pubmed-meshheading:19221509-Ion Channel Gating,
pubmed-meshheading:19221509-Membrane Potentials,
pubmed-meshheading:19221509-Models, Molecular,
pubmed-meshheading:19221509-Molecular Sequence Data,
pubmed-meshheading:19221509-Mutation,
pubmed-meshheading:19221509-Potassium,
pubmed-meshheading:19221509-Potassium Channels, Inwardly Rectifying,
pubmed-meshheading:19221509-Protein Conformation,
pubmed-meshheading:19221509-Protein Denaturation,
pubmed-meshheading:19221509-Protein Stability,
pubmed-meshheading:19221509-Protein Structure, Tertiary,
pubmed-meshheading:19221509-Protein Transport,
pubmed-meshheading:19221509-Rats,
pubmed-meshheading:19221509-Structure-Activity Relationship,
pubmed-meshheading:19221509-Transfection
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| pubmed:articleTitle |
The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating.
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| pubmed:affiliation |
Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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