Too much or too little iron in the body can lead to disease, but organisms have developed ways to keep iron levels in balance. Ferroportin, the only known source of iron that releases iron into the bloodstream, is a critical component of iron-balancing mechanisms.
In pursuit of a better understanding of iron regulation, a team led by researchers at Baylor College of Medicine analyzed the three-dimensional structure of a ferroportin mammalian animal, revealing unexpected properties and a novel modus operandi that could guide the development of innovative treatment strategies. The study shows in Nature Communications.
More than 60 mutations in the ferroportin gene have been linked to human diseases. Corresponding author Dr. Ming Zhu, Professor of Biochemistry and Molecular Biology Ruth McLean Bowman, said that some of these mutations make ferroportin insensitive to hepsidin, a peptide hormone synthesized in the liver that contributes to regulating the virus. Chu is also a member of the Dan L. Duncan Comprehensive Cancer Center in Baylor.
Ferroportin and hebsidine coordinate their activities to maintain iron balance in the body. Ferroportin releases iron into the blood, and hepsidin controls that exports do not exceed requirements. When hepsidin is not responding to ferroportin, it remains active. Consequently, the body is overloaded with iron, a condition called iron overload disease.
“We would like to better understand iron transport regulation by looking at the structure of ferroportin,” said co-first author Dr. Yaping Pan, Associate Professor of Biochemistry and Molecular Biology at Baylor. “Neither the ferroportin structure nor the ferroportin and hepcidin structure have been described together. A closer look at these structures will provide new insights into how ferroportin works and how hepsidin regulates its activity, opening possibilities for new approaches to treating hyper iron disease
Researchers studied ferroportin from the Philippine tarsier bird primate, which is more than 90 percent similar to that of human ferroportin. Previous studies that looked at bacterial ferroportin and other iron transporters showed that these proteins have only one iron binding site, carrying one iron group at a time.
“We started our study with the assumption that tarsier ferroportin also contains a single site for binding to iron, and I was baffled by the results of our experiments,” said senior co-author Jiemin Shen, a graduate student in quantitative and computational biological sciences in Zhou’s lab.
For example, the team conducted experiments to determine how changing the iron binding site affected the 3D structure of ferroportin. They piqued their curiosity when they found that the location change did not seem to have much effect, contrary to what they had expected. Once we revealed the structure of ferroportin with a cryogenic electron microscope, we realized that it had two iron-bound sites. This was a surprise that clarified the data that baffled us. “
“We were only changing one site and it looked like the other site was still bonding iron, so we didn’t see a major change in the ferroportin structure,” Shane said.
The second really exciting finding was that the mode of action of tarsier ferroportin differs from that reported for other iron transport companies, ”Chu said.
The iron ion exports of ferroportin carry two positive electric charges. We have found that when ferroportin emits iron ions, protons, which have a positive charge, are transported into the cell, balancing charges and facilitating the export of more iron, Pan said.
“We are using these new structural and functional results to identify small candidate molecules that can regulate ferroportin. We are also studying the two human viruses,” said Chu. “This project has good potential for translating the results to bed.”
Other contributors to this work include Zhenning Ren, Lie Wang, Zhichun Xu, Ye Yu, Preetham Bachina, and Hanzhi Zhang of Baylor College of Medicine; Shuai Gao, Xiao Fan, and Ning Yan at Princeton University, and Arthur Laganuski at Texas A&M University.
This work was supported by grants from the National Institutes of Health (DK122784, HL086392, and GM098878), the Institute of Cancer Prevention and Research of Texas (R1223), the Ara Parsigian Foundation for Medical Research, and the Shirley M. Tilgman Foundation professorships from Princeton University. Partial support was provided by the Princeton Center for Complex Materials and the National Science Foundation-MRSEC (DMR-1420541) program.
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