Media | Furthering knowledge of a potentially life-threatening prenatal condition

Diamond used in pre-eclampsia breakthrough

Researchers from the University of Cambridge have used Diamond Light Source to solve the 3D structure of a protein that plays a major role in hypertension in pre-eclampsia.

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Pre-eclampsia is a condition that occurs in around 5% of pregnancies, where the mother’s blood pressure increases (hypertension) and too much protein is leaked into the urine. It leads to the death of 10 women and 1,000 babies in the UK every year.There is currently no cure for the condition. The solution is to deliver the baby early as it is understood that pre-eclampsia is associated to a problem with the blood vessels in the placenta. Protein crystal structures solved at Diamond have led to a new insight into pre-eclampsia and the processes behind its main symptom, hypertension. In turn, this will lead to research into new therapies to combat the condition.

Human angiotensinogen on its own, with the peptide bond that would be cleaved by renin highlighted as a stick representation between the blue and green parts of the trace of the polypeptide chain. The peptide bond is buried and inaccessible to the protease.

Twenty years ago, along with his colleague Dr Penny Stein, Prof. Robin Carrell from the Department of Haematology at the Cambridge Institute for Medical Research (CIMR) embarked on a study of angiotensinogen, the “black sheep” of the serpin family since it is not known to inhibit other enzymes, unlike the rest of its family. With the help of synchrotron facilities, first Daresbury and now Diamond, Prof. Carrell and his colleagues have solved the 3D structure of angiotensinogen and made a breakthrough in understanding hypertension, in particular when it occurs during pregnancy and leads to pre-eclampsia.

Prof. Randy Read and Dr Aiwu Zhou from the Department of Haematology at the CIMR led the crystallography side of the study.

"Through solving the crystal structure of the proteins involved, we have uncovered new information on what is happening at the cellular level in the modulation of blood pressure in humans. Our work reveals evidence of a link between the oxidative changes in the placenta and the onset of hypertension, a defining feature of pre-eclampsia."

Prof. Randy Read, Department of Haematology at the CIMR

Through using Diamond’s macromolecular crystallography (MX) beamlines I02, I03 and I04, the group solved the 3D structure of the complex of angiotensinogen and renin, the enzyme responsible for releasing the protein that causes hypertension. Their beamtime led to an unsuspected discovery.

 

Complex of human angiotensinogen (right) with renin (left), showing how the conformation changes to expose the peptide bond that is cleaved, which is now in the active site of renin.
 
"Our results revealed what is in effect a fine-tuning mechanism at the commencement of the main process controlling blood pressure. We found that the activity of angiotensinogen is influenced by whether two sulphur atoms are linked by a disulphide bridge (in the oxidised state) or not (in the reduced state). The disulphide bridge readily undergoes a transition between the two forms. We determined, as proof of principle, that this is the case in pre-eclampsia and that the change in activity that occurs on oxidation in the placenta is a sufficient cause of pre-eclamptic hypertension. This breakthrough is largely thanks to protein crystallography. Knowing the 3D structures has transformed our understanding of the process controlling blood pressure."

Prof. Carrell, Department of Haematology at the CIMR

The group’s findings will reinforce efforts to develop therapies for pre-eclampsia and increase their efficacy.

Paper reference
Aiwu Zhou, Robin W. Carrell, Michael P. Murphy, Zhenquan Wei, Yahui Yan, Peter L. D. Stanley, Penelope E. Stein, Fiona Broughton Pipkin & Randy J. Read.
A redox switch in angiotensinogen modulates angiotensin release.
Nature. DOI: 10.1038/nature09505