Scientists discover the molecular origin of cystinosis, a rare genetic disease

Cystinosis, a rare genetic disease, is caused by mutations in the gene for a protein called cystinosine. A team of scientists has now solved the structure of cystinosine and determined how mutations interfere with its normal function, providing insights into the underlying mechanisms and suggesting a way to develop new treatments for the disease.

The new study, published on September 15 in Cellinvolved a collaborative effort between researchers from UC Santa Cruz, Stanford University, and the University of Texas Southwestern Medical Center, who combined their expertise in three specialized methods to study the structure and function of proteins: X-ray crystallography, cryogenic electron microscopy (cryo-EM), and double electron-electron resonance (DEER).

This article could define a model for how to combine these three domains, along with biochemical assays, to quickly refine how a protein works and identify a therapeutic strategy. »

Glenn Millhauser, Distinguished Professor and Chair of Chemistry and Biochemistry at UC Santa Cruz and corresponding author of the paper

Cystinosine is a specialized transport protein that plays a crucial role in how cells handle cysteine, an essential amino acid. Cells constantly recycle proteins, breaking them down into their constituent amino acids for use in building new proteins. Transporters like cystinosine move amino acids out of lysosomes – the cellular compartments where proteins are broken down – into the cell for reuse. When cystinosine doesn’t work properly due to mutations, a form of cysteine ​​(a dimer called cystine) builds up inside lysosomes.

Abnormal cystine buildup causes widespread damage to tissues and organs and can lead to kidney failure, muscle wasting, and other problems.

“It’s a rare disease, but it can be fatal,” Millhauser said. “If left untreated, people with cystinosis usually die before the age of ten.”

Cystinosine adopts different conformations when opened inward to the lysosome to load cystine and when opened outward to release cystine. Research teams from Stanford (led by Prof. Liang Feng) and UT Southwestern (led by Prof. Xiaochun Li) solved the structures of cystinosine in these different structural conformations using X-ray crystallography and cryo-EM.

However, understanding the structural changes of cystinosine through the transport process required the DEER studies performed by Millhauser’s laboratory. DEER is a specialized magnetic resonance technique that can be used to determine how a protein changes shape.

“With this, we were able to understand the mechanism that allows cystinosine to switch between these different states, and we were able to determine which of the amino acids in the protein was causing the transition,” Millhauser said. “We can now see how the mutations alter the protein’s ability to change shape and pump cystine out of the lysosome.”

This new insight into the molecular mechanics of cystinosine transport activity not only provides a more detailed understanding of the pathogenesis of cystinosis, but also suggests a possible therapeutic strategy to treat the disease. “It may be possible to enhance the transport activity of cystinosine by developing conformation-selective small molecules or biologics that promote an open conformation of the cytosol,” the authors wrote.

A similar approach could be used to target other transporter proteins, which are implicated in a wide range of diseases.

The paper’s authors include co-first authors Tufa Assafa at UC Santa Cruz, Xue Guo at Stanford, and Philip Schmiege at UT Southwestern, and co-authors Yan Xu at Stanford, Rong Wang, Linda Donnelly, and Michael Fine at UT Southwestern, and Xiaodan Ni and Jiansen Jiang at the National Heart, Lung, and Blood Institute. This work was funded in part by the National Institutes of Health.


University of California – Santa Cruz

Journal reference:

Guo, X. et al. (2022) Structure and mechanism of cystine-exporting human cystinosine. Cell.

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