Study shows chameleon-like protein can alter human brain

Neurons contain a chameleon-like protein that can alter its mind and, during the process, modifies the human brain.

Peter Wolynes, left, and Nicholas Schafer. Image Credit: Jeff Fitlow.

Now, a team of researchers from Rice University and the University of Texas Health Science Center at Houston (UTHealth) has found new clues in the CPEB3 protein as part of their steadfast pursuit of the mechanism that enables people to have long-term memories.

Performed by Peter Wolynes, a theoretical biophysicist from Rice University, and Neal Waxham, a neurobiologist from the McGovern Medical School at UTHealth, the study offers a better understanding of a positive feedback loop between the actin-binding domains in the CPEB3 protein and forming the actin backbones that provide flexibility and shape to the dendritic spines.

The CPEB3 protein is also a functional prion that attaches to RNA. This RNA, in turn, creates long-lasting aggregates that may certainly preserve the stuff that memories are made of.

Protein-folding models, created by Wolynes and his research team from Rice University’s Center for Theoretical Biological Physics (CTBP) as well as experiments conducted at UTHealth, revealed formerly unknown structural details for the CPEB3 protein and how it attaches to actin, as described in the Proceedings of the National Academy of Sciences paper.

During the process, the team also analyzed the major function of a protein, called SUMO, a regulator that attaches to and detaches from other kinds of proteins present in the cells to alter their functions.

The team believes that this regulator helps to control when and how the chameleon-like ends (the C-terminus and N-terminus) of the CPEB3 attach to either SUMO or the filamentous and flexible actin (f-actin) spines found in dendritic spikes.

The CPEB3 proteins become soluble when bound to SUMO, which also conceals their actin-binding locations. However, during synaptic activity, the CPEB3 proteins can be “deSUMOylated” and become available to attach with the hydrophobic-binding pockets along the f-actin filaments.

The protein-folding models revealed that when the CPEB3 protein is attracted to actin, it changes from a coiled-coil of helices into a beta-sheet structure. This structure “zips” into a hairpin configuration that causes it to aggregate with other CPEB3 proteins.

Once the CPEB3 protein aggregates, it seems to translate its target messenger RNAs containing actin mRNA that reinforces the synaptic junctions crucial to memory, concluding the positive loop.

This is a more ambitious project than the actin-CaM kinase study, where we also simulated a really huge actin system with a really huge protein.”

Peter Wolynes, Theoretical Biophysicist, Rice University

In that research work, which was published in 2019, the CTBP team modeled how a central protein, called CaMKII, holds parallel actin filaments jointly—a state that could be viewed in an electron microscope by Waxham’s laboratory.

The researchers are now defining the structural details that enable the CPEB3 protein to attach to either SUMO or actin, but not both.

One of the main aspects of this paper is to reconcile those two quite different parts of the story. We think the CPEB terminals are chameleonlike because they let the molecule choose whether it will interact with the SUMO or with the actin.”

Peter Wolynes, Theoretical Biophysicist, Rice University

“We’re not to the end of the story yet. But the latest results put us in a reasonable place to say more about the mechanism,” Wolynes concluded.

Researchers at Rice University modeled the binding structures of actin and associated proteins they believe are responsible for the formation of long-term memory. Here, the beta hairpin form of zipper sequence is a potential core for the formation of intramolecular beta sheets. In the predicted complex structure of F-actin and three PRD+ABD constructs shown above, the three PDB+ABD constructs are shown in rainbow color, from blue to red, from N-terminal to C terminal. The surfaces of first 4 negative residues of actin monomers are colored in red, and the surfaces of the two positive ends of the zipper sequence are colored in blue. Video Credit: Center for Theoretical Biological Physics/Rice University.