Two Clemson University groups are among the international team of researchers that developed a novel and technologically advanced approach that offers an unprecedented view of a protein linked to many neurological disorders.
The research, published by eLife in September, could potentially lay the groundwork for drug development to prevent or treat ischemic stroke, schizophrenia and autism.
The study involved Hugo Sanabria, associate professor in the Department of Physics and Astronomy; Physics Professor Feng Ding; George Hamilton, a former graduate student in Sanabria’s lab; and Nabanita Saikia, a former postdoctoral fellow in Feng’s group. Other participating researchers were from Stony Brook University and Heinrich Heine University.
Through the integration of advanced techniques, the scientists were able to show a dynamic view of the postsynaptic density protein 95 (PSD-95).
“The technique integrates both computation and actual experimentation probing different scales and that allows us to capture not only the structure of the molecule but also how it moves,” Ding said.
The human brain has billions of neurons that communicate via specialized connections called synapses.
PSD-95 is a scaffold protein positioned at neurons that receive chemical messages from adjacent neurons. By recruiting receptors and other helper proteins, PSD-95 works to maintain stable neural connections over time, thereby facilitating neural communication, learning and memory.
“One could call PSD-95 the glue molecule that brings multiple proteins together for the correct function of synapses,” Sanabria said. “It is responsible for assembling the machinery in a proper way so that the neurons can connect and function as they should.”
But when it doesn’t work properly, it can lead to disease.
PSD-95 consists of five parts, or domains, each of which plays a different role in the protein’s overall function by recruiting different players or proteins.
It is extremely dynamic and samples many different conformations in short timescales, making it difficult to accurately determine their structure and movement via traditional structural biology approaches.
To solve the problem, the researchers integrated state-of-the-art single molecule fluorescence-based and biochemical assays with molecular dynamics simulations to get an unprecedented dynamic view of the molecule.
The findings shed light on how protein-protein interactions select a particular molecule conformation.
PSD-95 is a drug target because it has been implicated in many neurological disorders, including ischemic stroke, schizophrenia and autism.
“PSD-95 has been pursued as a targetable protein because it interacts and regulates many targets implicated to neurological disorders, so you can almost tune the drugs for whatever the need is,” Sanabria said. “But in order to proceed with the drug discovery process, we need structural models of these proteins. Getting to know how PSD-95 looks and behaves has been a challenge because of its dynamic nature and architecture. In our work, we solved these problems and provided a mechanistic model of how the molecule really moves and how it interacts with one of the crucial partners in the synapse.”
To promote the usability of the structural models, researchers deposited them at the developmental database (PDB-dev) of the protein data bank. The archiving site provides free access to structural models.
Editors of eLife called the project’s research strategy “a textbook example to the field.”
The findings are of broad interest to investigators studying the function and regulation of protein scaffolds, dynamic protein structure and the regulation of the postsynaptic density at excitatory synapses, the reviewers said.
Findings of the study are detailed in the paper titled “Fuzzy supertertiary interactions within PSD-95 enable ligand binding.”
This research is supported by the National Institute of General Medical Sciences Award GM130451 and GM119691 and the National Science Foundation Award MCB1749778 and CBET15453945. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIGMS or the NSF.
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