KIF1A.ORG’s 22nd Research Roundtable meeting, “High-resolution structures of microtubule-bound KIF1A and its pathogenic variant P305L” was presented by Dr. Henando Sosa from the Albert Einstein College of Medicine. Let’s learn more about why understanding KIF1A structure is so important, and how it can inform new therapeutics.





Who Is Dr. Hernando Sosa?

Dr. Sosa is a researcher at the Albert Einstein College of Medicine, where he uses cutting-edge cryo-electron microscopy to investigate the structure of proteins with near-atomic resolution.

Last year, Dr. Sosa and fellow Research Network member Dr. Arne Gennerich received the 2022 Deerfield XSeed Award, a $100,000 grant, focused on developing therapeutics to treat KAND.


What is structural biology?

When your truck stops running properly, you might describe how it acts when you turn the ignition, the sounds it makes, or how it handles while driving.

While all of these can gives clues about the truck’s problems, you ultimately want a mechanic who can look at every part of the vehicle, tell you which specific part isn’t working, and how it impacts the rest of the truck. After all, you can’t fix what you don’t know about.

This is similar to our understanding KIF1A mutations. We know that mutations can cause KIF1A to move more slowly or quickly, or fall off of the microtubule roadways in our cells more often, or simply end up at the wrong destination. But to get to the mechanics of KIF1A biology, we need to look at KIF1A’s structure at the closest level of detail we can.

What do we mean by protein structure? If you were to stretch out a protein in a line, you could count up all of the amino acids one by one, and that would help you understand what the protein is made of. But this is similar to putting all the disassembled parts of a truck in a straight line – it’s not easy to see how the pieces fit together or how the truck runs unless you’re an expert mechanic.

Most proteins don’t exist as straight lines, they’re folded in specific ways to do their job, which we call the protein’s structure. Structural biologists like Dr. Sosa are the expert mechanics who look at exactly how the individual parts of a protein allow it to fold into its intended structure. This can help us learn more about how disease-related mutations cause dysfunction, and how we can correct that dysfunction!

High-resolution structures of microtubule-bound KIF1A and its pathogenic variant P305L

Dr. Sosa’s team used high resolution microscopy to determine the structure of KIF1A’s motor domain while it is attached to a microtubule, which allows them to see the working protein in more detail than ever before – this is big news for KIF1A researchers whose own projects can be better informed by KIF1A structure.

They then compared the structure of the KAND-related P305L mutation, which makes it harder for KIF1A to stay attached to the microtubule. This mutation causes a very subtle structural change in a nearby area of the protein, which Dr. Sosa’s team were able to partially fix by introducing a second mutation.

What does this mean for KAND? The hope is that by understanding KIF1A structure, we can develop structural therapeutics – chemicals that are custom-designed to fit into mutant KIF1A and fix the part that’s not working. Dr. Sosa and Dr. Gennerich are working with their teams to find potential structural therapeutics for the P305L mutation, and are planning to expand this search to other mutations soon.

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