Structural Insights into Binding of STAC Proteins to Voltage-Gated Calcium Channels
This week we profile a recent publication in PNAS from Dr. Filip Van Petegem
(third from left) and Siobhan Wong King Yuen (below) at UBC’s Life Sciences Institute.
Can you provide a brief overview of your lab’s current research focus?
We study the origins of cardiac arrhythmias, epilepsy, and specific muscle disorders. Although these conditions may seem very different at first, they have a lot in common, because they all affect electrical signals in the human body. Such signals are generated by ‘ion channels’, a specialized class of proteins that form pathways for charged ions to move in or out of a cell. The movement of these ions is what constitutes a primary electrical signal. As a result, mutations in the genes that encode ion channels can generate faulty electrical signals, which can have devastating consequences. The type of disease depends on the specific ion channel that is affected. For example, mutations in the genes for cardiac ion channels often result in heart rhythm disorders, whereas mutations in genes for neuronal ion channels can cause epilepsy or chronic pain. The questions we study are: how do these channels open and close? What molecules can bind these channels and trigger their opening? How does stress affect electrical signals? A major effort is done towards determining the 3D structures of the channels. By comparing structures of both ‘normal’ and ‘diseased’ channels, we can generate insights into the disease mechanisms. This, in turn, can help us decide how to interfere with them as part of a new therapeutic strategy. These channels are too small to be detected via regular microscopy, so we utilize very advanced techniques that make use of either X-rays or electrons. These methods allow us the locate every single atom in the channel 3D structures.
What is the significance of the findings in this publication?
The state of North Carolina is home for Lumbee Native Americans. Approximately 1 in 5000 people of this population are affected by a severe disorder known as ‘Native American Myopathy’. Patients have severe muscle weakness and developmental defects. The root cause is a mutation in a gene known as ‘STAC3‘. In this publication we studied the role of this protein and mapped the location of the genetic mutation on its 3D structure.
A more detailed explanation involves calcium. Mostly famous as constituents of bones and teeth, calcium ions have many other functions in the body. This includes muscle contraction: when calcium ions flow into the cytosol, the main compartment of the cell, a contraction is triggered. Two major ion channels are involved in this process: a ‘voltage-gated calcium channel’, which allows calcium ions to move inside the cell from the outside, and ‘Ryanodine Receptors’, allowing calcium ions to move out of an internal store. Very intriguing is how these two channels communicate: when one channel opens, the other one can sense it and open as well. This has been a long-standing biochemical puzzle, and it was unknown how these two channels, which are located in different compartments, can have mechanical interactions. But recently a new player has been found. A new protein known as ‘STAC3’ forms a glue that holds these two ion channels together. We determined the 3D structure of this molecular glue, and figured out how it engages the voltage-gated calcium channel. We also found the underlying basis for Native American Myopathy. The mutation knocks out the ability of STAC3 to connect and thus prevents the cross-talk between the two ion channels.
What are the next steps for this research?
We have figured out how STAC3 engages one of these two muscle ion channels, but not yet the other. In addition, new mutations have been found in the STAC3 genes of patients with muscle weakness. We thus aim to further dissect the interactions between STAC3 and the other ion channel, as well as map and characterize the new set of disease mutations.
This research was funded by:
This work was funded by CIHR.