scholarly journals Subunit exchange enhances information retention by CaMKII in dendritic spines

2018 ◽  
Author(s):  
Dilawar Singh ◽  
Upinder Singh Bhalla
Keyword(s):  
Protein Turnover ◽  
Information Storage ◽  
Memory Storage ◽  
Turnover Rates ◽  
Information Retention ◽  
Bistable Switch ◽  
Subunit Exchange ◽  
Calcium Calmodulin Dependent ◽  
Time Courses ◽  
Activity Decay

Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. CaMKII is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different microenvironments, the Post Synaptic Density (PSD) and spine cytosol. We show that in the PSD, subunit exchange leads to coordinated switching and prolongs state stability of the fraction of CaMKII that is present in clusters; and underlies spreading of activation among the remaining CaMKII that is uniformly distributed. Subunit exchange increases the robustness of the CaMKII switch measured as range of bistability both with respect to protein phosphatase 1 (PP1) levels and protein turnover rates. In the phosphatase-rich spine cytosol, subunit exchange leads to slower decay of activity following calcium stimuli. We find that subunit exchange can explain two time-courses of CaMKII activity decay observed in recent experiments monitoring endogenous activity of CaMKII in the spine. Overall, CaMKII exhibits multiple timescales of activity in the synapse and subunit exchange enhances the information retention ability of CaMKII by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks.Significance StatementDespite everyday forgetfulness, we can recall some memories years after they were formed. How are we able to protect some memories for so long? Previous work has shown that the abundant brain protein Calcium/calmodulin dependent protein Kinase II (CaMKII) can form a very stable binary switch which can store information for years. Building on this work, we analyzed the implications of a recently discovered phenomenon of subunit exchange on the state switching properties of CaMKII. In subunit exchange fragments of one CaMKII molecule detatch and exchange with another. We discovered that this improves the information retention ability of CaMKII both in the context where it stores information for long times, and also where it integrates information over the timescale of minutes.

scholarly journals Subunit exchange enhances information retention by CaMKII in dendritic spines

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Dilawar Singh ◽  
Upinder Singh Bhalla
Keyword(s):  
Information Storage ◽  
Memory Storage ◽  
Information Retention ◽  
Bistable Switch ◽  
Synaptic Density ◽  
Subunit Exchange ◽  
Calcium Calmodulin Dependent ◽  
Dependent Protein ◽  
The Stability

Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. Calcium/calmodulin-dependent protein Kinase II (CaMKII) is a highly expressed synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here, we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different micro-environments, the post synaptic density (PSD) and spine cytosol. We show that CaMKII exhibits multiple timescales of activity due to subunit exchange. Further, subunit exchange enhances information retention by CaMKII both by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks.

scholarly journals Influence of Subcellular Localization and Functional State on Protein Turnover

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1747
Author(s):  
Roya Yousefi ◽  
Kristina Jevdokimenko ◽  
Verena Kluever ◽  
David Pacheu-Grau ◽  
Eugenio F. Fornasiero
Keyword(s):  
Subcellular Localization ◽  
Functional State ◽  
Protein Turnover ◽  
Protein Localization ◽  
Small Gtpase ◽  
Turnover Rates ◽  
Cellular Behavior ◽  
Two Factors ◽  
Brain Creatine Kinase ◽  
Selection Of

Protein homeostasis is an equilibrium of paramount importance that maintains cellular performance by preserving an efficient proteome. This equilibrium avoids the accumulation of potentially toxic proteins, which could lead to cellular stress and death. While the regulators of proteostasis are the machineries controlling protein production, folding and degradation, several other factors can influence this process. Here, we have considered two factors influencing protein turnover: the subcellular localization of a protein and its functional state. For this purpose, we used an imaging approach based on the pulse-labeling of 17 representative SNAP-tag constructs for measuring protein lifetimes. With this approach, we obtained precise measurements of protein turnover rates in several subcellular compartments. We also tested a selection of mutants modulating the function of three extensively studied proteins, the Ca2+ sensor calmodulin, the small GTPase Rab5a and the brain creatine kinase (CKB). Finally, we followed up on the increased lifetime observed for the constitutively active Rab5a (Q79L), and we found that its stabilization correlates with enlarged endosomes and increased interaction with membranes. Overall, our data reveal that both changes in protein localization and functional state are key modulators of protein turnover, and protein lifetime fluctuations can be considered to infer changes in cellular behavior.

Protein turnover during metabolic arrest in turtle hepatocytes: role and energy dependence of proteolysis

1994 ◽  
Vol 266 (4) ◽  
pp. C1028-C1036 ◽  
Author(s):  
S. C. Land ◽  
P. W. Hochachka
Keyword(s):  
Energy Dependence ◽  
Protein Turnover ◽  
Lactate Production ◽  
Significant Inhibition ◽  
Turnover Rates ◽  
Atp Turnover ◽  
Protein Pool ◽  
Chrysemys Picta Bellii ◽  
Metabolic Arrest ◽  
Energy Dependent

Hepatocytes from the western painted turtle (Chrysemys picta bellii) are capable of a coordinated metabolic suppression of 88% during 10 h of anoxia at 25 degrees C. The energy dependence and role of proteolysis in this suppression were assessed in labile ([3H]Phe-labeled) and stable ([14C]Phe-labeled) protein pools. During anoxia, labile protein half-lives increased from 24.7 +/- 3.3 to 34.4 +/- 3.7 h, with stable protein half-lives increasing from 55.6 +/- 3.4 to 109.6 +/- 7.4 h. The total anoxic mean proteolytic suppression for both pools was 36%. On the basis of inhibition of O2 consumption and lactate production rates by cycloheximide and emetine, normoxic ATP-dependent proteolysis required 11.1 +/- 1.7 mumol ATP.g-1.h-1 accounting for 21.8 +/- 1.4% of total cellular metabolism. Under anoxia this was suppressed by 93% to 0.73 +/- 0.43 mumol ATP.g-1.h-1. Summation of this with protein synthesis ATP turnover rates indicated that under anoxia 45% of total ATP turnover rate was directed toward protein turnover. Studies with inhibitors of energy metabolism indicated that the majority of energy dependence was found in the stable protein pool, with no significant inhibition occurring among the more labile proteins. We conclude that proteolysis is largely energy dependent under normoxia, whereas under anoxia there is a shift to a slower overall proteolytic rate that is largely energy independent and represents loss mostly from the labile protein pool.

scholarly journals Dual pathways for ribonucleic acid turnover in WI-38 but not in I-cell human diploid fibroblasts.

1981 ◽  
Vol 1 (1) ◽  
pp. 75-81 ◽  
Author(s):  
M Sameshima ◽  
S A Liebhaber ◽  
D Schlessinger
Keyword(s):  
Ribosomal Rna ◽  
Ribonucleic Acid ◽  
Protein Turnover ◽  
Rna Turnover ◽  
Turnover Rates ◽  
Diploid Fibroblasts ◽  
Human Diploid Fibroblasts ◽  
Cytoplasmic Rna ◽  
Ribosomal Ribonucleic Acid ◽  
I Cells

The turnover rates of 3H-labeled 18S ribosomal ribonucleic acid (RNA), 28S ribosomal RNA, transfer RNA, and total cytoplasmic RNA were very similar in growing WI-38 diploid fibroblasts. The rate of turnover was at least twofold greater when cell growth stopped due to cell confluence, 3H irradiation, or treatment with 20 mM NaN3 or 2 mM NaF. In contrast, the rate of total 3H-protein turnover was the same in growing and nongrowing cells. Both RNA and protein turnovers were accelerated at least twofold in WI-38 cells deprived of serum, and this increase in turnover was inhibited by NH4Cl. These results are consistent with two pathways for RNA turnover, one of them being nonlysosomal and the other being lysosome mediated (NH4Cl sensitive), as has been suggested for protein turnover. Also consistent with the notion of two pathways for RNA turnover were findings with I-cells, which are deficient for many lysosomal enzymes, and in which all RNA turnover was nonlysosomal (NH4Cl resistant).

scholarly journals Gradation (approx. 10 size states) of synaptic strength by quantal addition of structural modules

2017 ◽  
Vol 372 (1715) ◽  
pp. 20160328 ◽  
Author(s):  
Kang K. L. Liu ◽  
Michael F. Hagan ◽  
John E. Lisman
Keyword(s):  
Functional Module ◽  
Late Phase ◽  
Matrix Material ◽  
Super Resolution ◽  
Long Term Potentiation ◽  
Information Storage ◽  
Homeostatic Plasticity ◽  
Memory Storage ◽  
Long Term Memory

Memory storage involves activity-dependent strengthening of synaptic transmission, a process termed long-term potentiation (LTP). The late phase of LTP is thought to encode long-term memory and involves structural processes that enlarge the synapse. Hence, understanding how synapse size is graded provides fundamental information about the information storage capability of synapses. Recent work using electron microscopy (EM) to quantify synapse dimensions has suggested that synapses may structurally encode as many as 26 functionally distinct states, which correspond to a series of proportionally spaced synapse sizes. Other recent evidence using super-resolution microscopy has revealed that synapses are composed of stereotyped nanoclusters of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and scaffolding proteins; furthermore, synapse size varies linearly with the number of nanoclusters. Here we have sought to develop a model of synapse structure and growth that is consistent with both the EM and super-resolution data. We argue that synapses are composed of modules consisting of matrix material and potentially one nanocluster. LTP induction can add a trans-synaptic nanocluster to a module, thereby converting a silent module to an AMPA functional module. LTP can also add modules by a linear process, thereby producing an approximately 10-fold gradation in synapse size and strength. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

scholarly journals Architecture and mechanism of the central gear in an ancient molecular timer

2017 ◽  
Vol 14 (128) ◽  
pp. 20161065 ◽  
Author(s):  
Martin Egli
Keyword(s):  
Clock Synchronization ◽  
Three Dimensional ◽  
Memory Storage ◽  
Dimensional Structure ◽  
Molecular Clocks ◽  
Subunit Exchange ◽  
Architectural Features ◽  
Long Time ◽  
Central Gear

Molecular clocks are the product of natural selection in organisms from bacteria to human and their appearance early in evolution such as in the prokaryotic cyanobacterium Synechococcus elongatus suggests that these timers served a crucial role in genetic fitness. Thus, a clock allows cyanobacteria relying on photosynthesis and nitrogen fixation to temporally space the two processes and avoid exposure of nitrogenase carrying out fixation to high levels of oxygen produced during photosynthesis. Fascinating properties of molecular clocks are the long time constant, their precision and temperature compensation. Although these are hallmarks of all circadian oscillators, the actual cogs and gears that control clocks vary widely between organisms, indicating that circadian timers evolved convergently multiple times, owing to the selective pressure of an environment with a daily light/dark cycle. In S. elongatus , the three proteins KaiA, KaiB and KaiC in the presence of ATP constitute a so-called post-translational oscillator (PTO). The KaiABC PTO can be reconstituted in an Eppendorf tube and keeps time in a temperature-compensated manner. The ease by which the KaiABC clock can be studied in vitro has made it the best-investigated molecular clock system. Over the last decade, structures of all three Kai proteins and some of their complexes have emerged and mechanistic aspects have been analysed in considerable detail. This review focuses on the central gear of the S. elongatus clock and only enzyme among the three proteins: KaiC. Our determination of the three-dimensional structure of KaiC early in the quest for a better understanding of the inner workings of the cyanobacterial timer revealed its unusual architecture and conformational differences and unique features of the two RecA-like domains constituting KaiC. The structure also pinpointed phosphorylation sites and differential interactions with ATP molecules at subunit interfaces, and helped guide experiments to ferret out mechanistic aspects of the ATPase, auto-phosphorylation and auto-dephosphorylation reactions catalysed by the homo-hexamer. Comparisons between the structure of KaiC and those of nanomachines such as F1-ATPase and CaMKII also exposed shared architectural features (KaiC/ATPase), mechanistic principles (KaiC/CaMKII) and phenomena, such as subunit exchange between hexameric particles critical for function (clock synchronization, KaiABC; memory-storage, CaMKII).

scholarly journals Protein turnover rates of two human subjects during an unassisted crossing of Antarctica

1996 ◽  
Vol 76 (2) ◽  
pp. 165-174 ◽  
Author(s):  
M. A. Stroud ◽  
A. A. Jackson ◽  
J. C. Waterlow
Keyword(s):  
Protein Synthesis ◽  
Protein Turnover ◽  
Human Subjects ◽  
Austral Summer ◽  
High Energy ◽  
Turnover Rates ◽  
Energy Expenditures ◽  
Combined Stresses ◽  
Freeze Dried ◽  
Product Method

During the Austral summer of 1992–3, two men, MS and RF, walked 2300 km across Antarctica in 96 d, unassisted by other men, animals or machines. During the journey they ate freeze-dried rations, towed on sledges, that contained an average of 21·3 MJ/d of which 56·7% was fat, 35·5% carbohydrate and 7·8% protein (98·8 g). Despite this high energy intake both men lost more than 20 kg in body weight due to their extremely high energy expenditures. Studies of protein turnover using [15N]glycine by the single-dose end-product method were made before, during and after the journey, and these demonstrated considerable differences in the metabolic responses of the two men to the combined stresses of exercise, cold and undernutrition. However, both men maintained high and relatively stable levels of protein synthesis during the expedition despite the great exertion and the onset of considerable debilitation. This stability indicates the vital physiological function of protein synthesis.

PROTEIN TURNOVER IN WHEAT AND SNAPDRAGON LEAVES: PRELIMINARY INVESTIGATIONS

1963 ◽  
Vol 41 (7) ◽  
pp. 969-983 ◽  
Author(s):  
J. A. Hellebust ◽  
R. G. S. Bidwell
Keyword(s):  
Amino Acids ◽  
Protein Turnover ◽  
Soluble Sugars ◽  
Turnover Rates ◽  
Time Intervals ◽  
Protein Nitrogen ◽  
Protein Amino Acids ◽  
Specific Activities ◽  
Wheat Leaves ◽  
Biochemical Differentiation

Detached primary wheat leaves and attached cotyledons and primary leaves of snapdragons were allowed to photoassimilate C14O2 for short periods of time. They were subsequently kept in air and samples were taken at various time intervals and analyzed for protein nitrogen, and amounts and total radioactivities of soluble sugars and amino acids and protein amino acids. A method of estimating protein turnover from these data is discussed. Amounts and specific activities of respired carbon were also determined for wheat leaves.Minimum protein turnover rates of about 0.5 to 1.5% per hour were found in rapidly growing snapdragon leaves and in snapdragon cotyledons. Lower rates were found in detached, non-growing wheat leaves and slowly growing snapdragon leaves. Little contribution could have been made by proteins as substrates for respiration in detached wheat leaves. It is suggested that protein turnover in leaves is mainly associated with growth and biochemical differentiation.

scholarly journals Versatile proteome labelling in fruit flies with SILAF

2019 ◽  
Author(s):  
Florian A. Schober ◽  
Ilian Atanassov ◽  
David Moore ◽  
Anna Wedell ◽  
Christoph Freyer ◽  
...  
Keyword(s):  
Protein Turnover ◽  
Cell Biology ◽  
Metabolic Regulation ◽  
Developmental Stages ◽  
Fruit Fly ◽  
Phosphorylation Sites ◽  
Turnover Rates ◽  
Post Translational Modification ◽  
Stable Isotope Labelling ◽  
Rapid Generation

ABSTRACTDrosophila melanogaster has been a working horse of genetics and cell biology for more than a century. However, proteomic-based methods have been limited due to technical obstacles, especially the lack of reliable labelling methods. Here, we advanced a chemically defined food source into stable-isotope labelling of amino acids in flies (SILAF). It allows for the rapid generation of a large number of flies with full incorporation of lysine-6. SILAF followed by fractionation and enrichment gave proteomic insights at a depth of 5,966 proteins and 7,496 phosphorylation sites, which substantiated metabolic regulation on enzymatic level. Furthermore, the label can be traced and predicts protein turnover rates during different developmental stages. The ease and versatility of the method actuates the fruit fly as an appealing model in proteomic and post-translational modification studies and it enlarges potential metabolic applications based on heavy amino acid diets.

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