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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Loukin, Stephen H. Kung, Ching Teng, Jinfeng |
| Description | Author Affiliation: Loukin SH ( Laboratory of Molecular Biology, University of Wisconsin, Madison, WI 53706); Teng J ( Laboratory of Molecular Biology, University of Wisconsin, Madison, WI 53706); Kung C ( Laboratory of Molecular Biology, University of Wisconsin, Madison, WI 53706); |
| Abstract | $Ca^{2+}-calmodulin$ (CaM) regulates varieties of ion channels, including Transient Receptor Potential vanilloid subtype 4 (TrpV4). It has previously been proposed that internal $Ca^{2+}$ increases TrpV4 activity through $Ca^{2+}-CaM$ binding to a C-terminal $Ca^{2+}-CaM$ binding domain (CBD). We confirmed this model by directly presenting $Ca^{2+}-CaM$ protein to membrane patches excised from TrpV4-expressing oocytes. Over 50 TRPV4 mutations are now known to cause heritable skeletal dysplasia (SD) and other diseases in human. We have previously examined 14 SD alleles and found them to all have gain-of-function effects, with the gain of constitutive open probability paralleling disease severity. Among the 14 SD alleles examined, E797K and P799L are located immediate upstream of the CBD. They not only have increase basal activity, but, unlike the wild-type or other SD-mutant channels examined, they were greatly reduced in their response to $Ca^{2+}-CaM.$ Deleting a 10-residue upstream peptide (Δ795–804) that covers the two SD mutant sites resulted in strong constitutive activity and the complete lack of $Ca^{2+}-CaM$ response. We propose that the region immediately upstream of CBD is an autoinhibitory domain that maintains the closed state through electrostatic interactions, and adjacent detachable $Ca^{2+}-CaM$ binding to CBD sterically interferes with this autoinhibition. This work further supports the notion that TrpV4 mutations cause SD by constitutive leakage. However, the closed conformation is likely destabilized by various mutations by different mechanisms, including the permanent removal of an autoinhibition documented here. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 30 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-07-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Bone Diseases Physiopathology Calmodulin Chemistry Channelopathies TRPV Cation Channels Physiology Alleles Amino Acid Sequence Animals Binding Sites Genetics Calcium Chelating Agents Gene Expression Profiling Ion Channel Gating Molecular Sequence Data Mutation Oocytes Cytology Protein Binding Protein Structure, Tertiary RNA, Complementary Metabolism Sequence Homology, Amino Acid Xenopus Laevis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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