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- W4378640147 endingPage "102752" @default.
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- W4378640147 abstract "Calmodulin (CaM) is a ubiquitous, calcium-sensing protein that regulates a multitude of processes throughout the body. In response to changes in [Ca2+], CaM modifies, activates, and deactivates enzymes and ion channels, as well as many other cellular processes. The importance of CaM is highlighted by the conservation of an identical amino acid sequence in all mammals. Alterations to CaM amino acid sequence were once thought to be incompatible with life. During the last decade modifications to the CaM protein sequence have been observed in patients suffering from life-threatening heart disease (calmodulinopathy). Thus far, inadequate or untimely interaction between mutant CaM and several proteins (LTCC, RyR2, and CaMKII) have been identified as mechanisms underlying calmodulinopathy. Given the extensive number of CaM interactions in the body, there are likely many consequences for altering CaM protein sequence. Here, we demonstrate that disease-associated CaM mutations alter the sensitivity and activity of the Ca2+-CaM-enhanced serine/threonine phosphatase calcineurin (CaN). Biophysical characterization by circular dichroism, solution NMR spectroscopy, stopped-flow kinetic measurements, and MD simulations provide mechanistic insight into mutation dysfunction as well as highlight important aspects of CaM Ca2+ signal transduction. We find that individual CaM point mutations (N53I, F89L, D129G, and F141L) impair CaN function, however, the mechanisms are not the same. Specifically, individual point mutations can influence or modify the following properties: CaM binding, Ca2+ binding, and/or Ca2+kinetics. Moreover, structural aspects of the CaNCaM complex can be altered in manners that indicate changes to allosteric transmission of CaM binding to the enzyme active site. Given that loss of CaN function can be fatal, as well as evidence that CaN modifies ion channels already associated with calmodulinopathy, our results raise the possibility that altered CaN function contributes to calmodulinopathy." @default.
- W4378640147 created "2023-05-30" @default.
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- W4378640147 date "2023-07-01" @default.
- W4378640147 modified "2023-10-10" @default.
- W4378640147 title "Human disease-associated calmodulin mutations alter calcineurin function through multiple mechanisms" @default.
- W4378640147 cites W1546431662 @default.
- W4378640147 cites W1571243084 @default.
- W4378640147 cites W1866700903 @default.
- W4378640147 cites W1963637372 @default.
- W4378640147 cites W1965699935 @default.
- W4378640147 cites W1968984443 @default.
- W4378640147 cites W1970331854 @default.
- W4378640147 cites W1971072760 @default.
- W4378640147 cites W1974019900 @default.
- W4378640147 cites W1975107946 @default.
- W4378640147 cites W1976499671 @default.
- W4378640147 cites W1982218909 @default.
- W4378640147 cites W1983814120 @default.
- W4378640147 cites W1986656675 @default.
- W4378640147 cites W1986965144 @default.
- W4378640147 cites W1987159249 @default.
- W4378640147 cites W1988146103 @default.
- W4378640147 cites W1989745031 @default.
- W4378640147 cites W1989873586 @default.
- W4378640147 cites W1990622494 @default.
- W4378640147 cites W2020612427 @default.
- W4378640147 cites W2027380922 @default.
- W4378640147 cites W2029870632 @default.
- W4378640147 cites W2041360509 @default.
- W4378640147 cites W2049629965 @default.
- W4378640147 cites W2052863274 @default.
- W4378640147 cites W2056857490 @default.
- W4378640147 cites W2069187446 @default.
- W4378640147 cites W2080169144 @default.
- W4378640147 cites W2086141071 @default.
- W4378640147 cites W2087062865 @default.
- W4378640147 cites W2096716204 @default.
- W4378640147 cites W2097575249 @default.
- W4378640147 cites W2100681932 @default.
- W4378640147 cites W2103445003 @default.
- W4378640147 cites W2104571730 @default.
- W4378640147 cites W2115812446 @default.
- W4378640147 cites W2116234307 @default.
- W4378640147 cites W2118901204 @default.
- W4378640147 cites W2120601131 @default.
- W4378640147 cites W2130124702 @default.
- W4378640147 cites W2130401575 @default.
- W4378640147 cites W2131058598 @default.
- W4378640147 cites W2132180320 @default.
- W4378640147 cites W2139214355 @default.
- W4378640147 cites W2147022900 @default.
- W4378640147 cites W2149138461 @default.
- W4378640147 cites W2156433522 @default.
- W4378640147 cites W2158254702 @default.
- W4378640147 cites W2160778262 @default.
- W4378640147 cites W2163684298 @default.
- W4378640147 cites W2332712348 @default.
- W4378640147 cites W2335852171 @default.
- W4378640147 cites W2337942016 @default.
- W4378640147 cites W2343603404 @default.
- W4378640147 cites W2404280981 @default.
- W4378640147 cites W2538466402 @default.
- W4378640147 cites W2547562734 @default.
- W4378640147 cites W2607152676 @default.
- W4378640147 cites W2743942560 @default.
- W4378640147 cites W2759936797 @default.
- W4378640147 cites W2794850100 @default.
- W4378640147 cites W2890277829 @default.
- W4378640147 cites W2904336918 @default.
- W4378640147 cites W2921459374 @default.
- W4378640147 cites W2953950496 @default.
- W4378640147 cites W2954594722 @default.
- W4378640147 cites W2966293790 @default.
- W4378640147 cites W2971656217 @default.
- W4378640147 cites W2971838170 @default.
- W4378640147 cites W3008286410 @default.
- W4378640147 cites W3120349139 @default.
- W4378640147 cites W3136891117 @default.
- W4378640147 cites W3138459642 @default.
- W4378640147 cites W3196048293 @default.
- W4378640147 cites W3202649610 @default.
- W4378640147 cites W4233503959 @default.
- W4378640147 cites W4315619340 @default.