First structure of human protein complex with 'license to kill'

Date:
December 10, 2021
Source:
Walter and Eliza Hall Institute
Summary:
A team of researchers has for the first time visualized a human cell
death complex linked to autoimmune and inflammatory conditions,
such as inflammatory bowel disease, and injuries associated with
excessive cell death.



FULL STORY ==========================================================================
A team of WEHI researchers has for the first time visualised a human cell
death complex linked to autoimmune and inflammatory conditions, such
as inflammatory bowel disease, and injuries associated with excessive
cell death.


========================================================================== Using the Australian Synchrotron, the team solved the structure of the
human cell death proteins MLKL and RIPK3 bound to each other, as well
as human RIPK3 alone. When RIPK3 activates MLKL, it triggers a type of inflammatory cell death called necroptosis that kills the cell and alerts
the immune system that it is under attack. However, when uncontrolled, necroptosis has been linked to human inflammatory diseases.

The findings will help scientists discover drugs that can target and
suppress cell death by necroptosis, which could lead to new treatments
for a range of autoimmune and inflammatory diseases including inflammatory bowel disease, renal injury and diabetes.

The research, published in the journal Nature Communications, was led by
WEHI researchers Yanxiang Meng, Dr Katherine Davies, Associate Professor
Peter Czabotar and Associate Professor James Murphy. The discovery is
the latest in an almost 15-year-long journey to understand necroptosis
for treating disease.

At a glance
* WEHI researchers have visualised the structures of human cell death
protein RIPK3 alone, and RIPK3 bound to MLKL in a dormant state.

*

=========================================================================
It is the first time these cell death proteins in humans have
been visualised alone and in complex, giving scientists a visual
understanding of what triggers the dormant complex to activate
and kill cells.

* The research has the potential to lead to new therapies for
conditions
associated with excessive inflammatory cell death, such as
inflammatory bowel disease, ischaemia-reperfusion injury in kidney
and heart tissues, and diabetes.

'The cell death pathway' Necroptosis is a type of inflammatory cell
death process that helps protect the body against infection. Most often triggered when a cell is infected by a virus or bacteria, the cell
is instructed to die and send inflammatory signals to warn the immune
system of foreign invaders. However, when necroptosis is uncontrolled
or excessive, the inflammatory response can trigger disease.

PhD student Yanxiang Meng said that MLKL and RIPK3 are bound in an inert
state in all cells of the body, waiting to be activated.



========================================================================== "MLKL and RIPK3 form an inert complex, with RIPK3 'holding' MLKL in an
inactive state to prevent necroptotic cell death," he said.

"When the cell is infected, RIPK3 chemically modifies MLKL then detaches, giving it a 'licence to kill' the infected or damaged cell for the
greater good," he said.

He said the Australian Synchrotron and Collaborative Crystallisation
Centre (C3) facility at CSIRO were crucial to visualise the structure
of human forms of RIPK3 bound to human MLKL for the first time.

"The necroptotic cell death proteins are conserved across different
organisms, however there are differences between the proteins' structures
in different animals and how they bind to each other.

"We showed that the human versions of these proteins bind differently
to what we have seen in other species.

"This is something the scientific community has been waiting many years
for." New targets for drug discovery Dr Davies said the team hoped this structural information would, in the future, lead to new treatment options
for patients suffering from diseases linked to excessive necroptosis.

"We now have a picture of how two key proteins in this death pathway
are maintained in their dormant state. It would be interesting to know
how this is regulated and leads to disease and whether this could be
targeted with small molecule drugs," she said.

The research was supported by ACRF, Australian Government National
Health and Medical Research Council and Department of Education, Skills
and Employment, Australian Institute of Nuclear Science and Engineering
(AINSE) Postgraduate Research Award, Melbourne Research Scholarship,
Wendy Dowsett Scholarship, and the Victorian Government.

========================================================================== Story Source: Materials provided by Walter_and_Eliza_Hall_Institute. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Yanxiang Meng, Katherine A. Davies, Cheree Fitzgibbon, Samuel
N. Young,
Sarah E. Garnish, Christopher R. Horne, Cindy Luo, Jean-Marc
Garnier, Lung-Yu Liang, Angus D. Cowan, Andre L. Samson,
Guillaume Lessene, Jarrod J. Sandow, Peter E. Czabotar & James
M. Murphy. Human RIPK3 maintains MLKL in an inactive conformation
prior to cell death by necroptosis.

Nature Communications, 2021 DOI: 10.1038/s41467-021-27032 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211210103143.htm

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