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|Title: ||Cool-temperature-mediated activation of phospholipase C-[gamma]2 in the human hereditary disease PLAID|
|Authors: ||Schade, Anja|
Kraus, Johann M.
Kestler, Hans A.
Milner, Joshua D.
|Keywords: ||Phospholipase C-[gamma]2|
Split pH domain
Cold temperature sensitivity
|Issue Date: ||2016|
|Publisher: ||© Elsevier|
|Citation: ||SCHADE, A. ... et al., 2016. Cool-temperature-mediated activation of phospholipase C-[gamma]2 in the human hereditary disease PLAID. Cellular Signalling, DOI: 10.1016/j.cellsig.2016.05.010.|
|Abstract: ||Deletions in the gene encoding signal-transducing inositol phospholipid-specific phospholipase C-[gamma]2 (PLC[gamma]2) are associated with the novel human hereditary disease PLAID (PLC[gamma]2-associated antibody deficiency and immune dysregulation). PLAID is characterized by a rather puzzling concurrence of augmented and diminished functions of the immune system, such as cold urticaria triggered by only minimal decreases in temperature, autoimmunity, and immunodeficiency. Understanding of the functional effects of the genomic alterations at the level of the affected enzyme, PLC[gamma]2, is currently lacking. PLC[gamma]2 is critically involved in coupling various cell surface receptors to regulation of important functions of immune cells such as mast cells, B cells, monocytes/macrophages, and neutrophils. PLC[gamma]2 is unique by carrying three Src (SH) and one split pleckstrin homology domain (spPH) between the two catalytic subdomains (spPHn-SH2n-SH2c-SH3-spPHc). Prevailing evidence suggests that activation of PLC[gamma]2 is primarily due to loss of SH-region-mediated autoinhibition and/or enhanced plasma membrane translocation. Here, we show that the two PLAID PLC[gamma]2 mutants lacking portions of the SH region are strongly (> 100-fold), rapidly, and reversibly activated by cooling by only a few degrees. We found that the mechanism(s) underlying PLC[gamma]2 PLAID mutant activation by cool temperatures is distinct from a mere loss of SH-region-mediated autoinhibition and dependent on both the integrity and the pliability of the spPH domain. The results suggest a new mechanism of PLC[gamma] activation with unique thermodynamic features and assign a novel regulatory role to its spPH domain. Involvement of this mechanism in other human disease states associated with cooling such as exertional asthma and certain acute coronary events appears an intriguing possibility.|
|Description: ||This item will remain closed access until 18/05/2017.|
|Version: ||Accepted for publication|
|Publisher Link: ||http://dx.doi.org/10.1016/j.cellsig.2016.05.010|
|Appears in Collections:||Closed Access (Design School)|
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