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First 3D map of cell-building protein linked to cancer

 
ACRF
ACRF
August 23, 2016

Cancer researchers at Walter and Eliza Hall Institute (WEHI) and Olivia Newton-John Cancer Research Institute in Melbourne have revealed for the first time a three-dimensional molecular ‘map’ of a protein that has been pinpointed as a driver of many types of cancers.

The unprecedented view of the protein doublecortin kinase like domain 1 (DCLK1) could provide clues to how it contributes to cancer formation and progression. This could lead to new cancer treatments in the future.

DCLK1 is a protein that assembles scaffolds within cells called microtubules. These rope-like structures give cells shape, enable movement and cell division, and are crucial in enabling the growth and spread of cancer cells. More than one in 10 stomach cancers have defective forms of DCLK1, which have also been found in kidney, rectal and pancreatic cancers.

The research team used the Australian Synchrotron to reveal the three-dimensional structure of a part of DCLK1 known as the ‘kinase domain’. They were able to pinpoint the parts of DCLK1 that can go wrong in cancer cells, providing new information about how the protein functions.

Dr Isabelle Lucet at WEHI said in healthy cells, DCLK1 can control its own function, ensuring it only assembles microtubules at the right time.

“We can think of the kinase domain of DCLK being an inbuilt controlling unit. The kinase domain sits separately from the part of the protein that assembles microtubules, and can switch microtubule assembly on or off as needed.”

“The complexity of having these two different components in one protein has, until now, hindered our understanding of how DCLK1 functions normally and what goes wrong in cancer. We decided to focus on just the regulatory kinase domain of DCLK1, because we knew that this is the part of DCLK1 that is often altered in cancers,” Dr Lucet said.

Dr Onisha Patel at WEHI said the team created a detailed map of the DCLK1 kinase domain using the Australian Synchrotron, providing new information about how the part of the protein functioned.

“By looking at the structure of the kinase domain at the atomic level, we can now understand the effect of cancer-associated mutations located in this region,” she said.

“These mutations can lead to a non-stop microtubule building by DCLK1, and consequently chaotic cell division that is a hallmark of cancer.”

“The protein structure we have generated allows us to pinpoint a crucial three dimensional pocket within DCLK1. We hope this will provide a first step towards designing a drug that will precisely target DCLK1, and prevent it from driving cancer growth. Similar protein structures have been used to design anti-cancer agents that are now in clinical use, so we’re hopeful that our research may have similar applications into the future,” Dr Patel said.

The research was recently published in the journal Structure.

The research was supported by the Australian Research Council, the Australian Cancer Research Foundation, National Health and Medical Research Council and the Victorian Government Operational Infrastructure Support Scheme.

This news article was first published on the WEHI website. Image of the research team courtesy of WEHI.

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