Brain complexity: memory formation (Introduction)

by David Turell , Monday, August 26, 2019, 23:55 (1916 days ago) @ David Turell

Special proteins joining with actin which is part of almost all cells:

https://phys.org/news/2019-08-scientists-advance-memory-molecular-roots.html

"A new piece of a difficult puzzle—the nature of memory—fell into place this week with a hint at how brain cells change structure when they learn something.

"Interactions between three moving parts—a binding protein, a structural protein and calcium—are part of the process by which electrical signals enter neural cells and remodel the molecular structures thought to enable cognition and the storage of memories.

"Colleagues from Rice University, the University of Houston (UH) and The University of Texas Health Science Center at Houston (UTHealth) combined theories, simulations and experiments to determine how a central binding protein—calcium-calmodulin-dependent kinase II (CaMKII)—binds and unbinds from the cytoskeleton of a neuron.

"The team's report in the Proceedings of the National Academy of Sciences gives the first clear details of how the binding sites of CaMKII act to align actin filaments—the structural protein—into long, rigid bundles. The bundles serve as the supporting skeletons of dendritic spines, spiky protrusions that receive chemical messages through synapses from other neurons.

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"When combined with the actin that makes up the cytoskeleton, the system also became the largest protein Wolynes and his team have analyzed via their protein-structure prediction program, AWSEM.

"When they were done, the structure predicted by the computer was a remarkable match for two-dimensional electron microscope images by Waxham and his group that clearly show parallel actin filaments are held together, ladder-like, by rungs of CaMKII.

"'There definitely are preliminary chemical steps involving the enzyme activity of CaMKII before you get to this stage; therefore, we don't have a completely clear picture of how to put everything together," Wolynes said. "But it's clear the assembly of the complex is the key step where chemistry turns into a larger-scale structure that can hold a memory."

"CaMKII is uniquely suited to interact with actin, the most abundant protein in eukaryotic cells and one that has special abilities in neurons, where it not only has to give thousands of dendrites (in each of billions of neurons) their resting forms but also must give them a level of plasticity to adapt to a constant barrage of signals.

"Actin molecules self-assemble into long, twisting filaments. The hydrophobic pockets between these molecules are perfectly configured to bind CaMKII, a large protein with multiple parts, or domains. These domains lock in to three consecutive binding sites on the filament, and the twists put binding sites at regular intervals to keep the proteins from piling up.

"CaMKII's "association" domain is a six-fold subunit that also binds to adjacent filaments to form actin bundles, the backbones of dendritic spines that give these protrusions their shapes.

"These bundles remain rigid if the dendrite contains little calcium. But when calcium ions enter through the synapse, they combine with calmodulin proteins, allowing them to bind to another part of CaMKII, the floppy regulatory domain. That triggers the disassociation of a domain of CaMKII from the filament, followed by the rest of the protein, opening a short window of time during which the bundles can reconfigure.

"'When enough calcium comes in, the activated calmodulin breaks up these structures, but only for a while," Wolynes said. "Then the cytoskeleton reforms. During that time, the dendritic spine can take on a different shape that might be bigger."

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"The team's calculations showed the association domain is responsible for about 40% of the protein's binding strength to actin. A linker domain adds another 40% and the crucial regulatory domain provides the final 20%—a sensible strategy, since the regulatory domain is on the lookout for incoming calcium-calmodulins that can unzip the entire protein from the filament."

Comment: Only partially understood, but the research field has revealed the underlying very complex proteins which hold the key. Look at the diagrams of this enormous molecular structure. Not put together by chance.