Structural and biophysical studies of human cystinosine reveal the molecular mechanisms and conformational dynamics of the transport of proton-conjugated lysosomal amino acids. Credit: Guo et al. , cell 2022
The rare hereditary cystinosis is caused by mutations in the gene for a protein called cystinosin. A team of scientists has now resolved the structure of cystinocine and determined how the mutations interfere with its normal function, providing insight into the underlying mechanisms and suggesting a way to develop new treatments for the disease.
The new study, published September 15 in cellshare a collaborative effort by researchers at the University of California, Santa Cruz, Stanford University, and the University of Texas Southwestern Medical Center, who combined their expertise in three specialized methods of study Protein Structure Function: X-ray crystallography, cryogenic electron microscopy (cryo-EM), and double electron resonance (DEER).
“This paper can model how to combine these three areas, along with biochemical assays, to quickly narrow down how a protein works and determine a therapeutic strategy,” said Glenn Millhauser, Distinguished Professor and Chair of the Department of Chemistry and Biochemistry at UCLA. Santa Cruz and corresponding author of the paper.
Cystinosin is a specialized transporter protein that plays an important role in how cells manage the essential amino acid cysteine. Cells are constantly recycling proteins, breaking them down into their constituent amino acids for use in building new proteins. Transporters such as cystenosine transport amino acids out of the lysosomes – the cellular parts where proteins are broken down – into the cell for reuse. When cystinocine does not function properly due to mutations, a form of cysteine (a dimer called cysteine) accumulates within the lysosomes.
The abnormal buildup of cysteine causes extensive 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 it is not treated, people with cystinosis usually die by the age of 10.”
Cystine adopts different conformations when it is open inward to the lysosome to load cysteine and when it is open outward to release cysteine. Research teams at Stanford University (led by Professor Liang Feng) and at Southwestern University (led by Professor Xiaochun Li) have solved cystenosine structures in these different structural conformations using X-ray crystallography and cryo-EM.
However, understanding the structural changes of cystinocine through the transport process requires DEER studies conducted by the Millhauser Laboratory. DEER is a specialized MRI technique that can be used to determine how a protein changes its shape.
“With this we were able to figure out the mechanism that allows cystinosine to switch between those different states, and we can narrow down which amino acid of the protein was driving the shift,” Millhauser said. “We can now see how the mutations alter the protein’s ability to change shape and pump cysteine out of the lysosome.”
These new insights into the molecular mechanics of cystinosine transporter activity not only provide a more detailed understanding of cystinosis pathogenesis, but also suggest a potential therapeutic strategy for treating the disease. “It may be possible to enhance cystinosine transporter activity by developing conformation-selective small molecules or biomaterials that favor open cell conformation,” the authors wrote.
A similar approach can be used to target other carrier proteins, which are involved in a wide range of diseases.
Xue Guo et al, Structure and mechanism of human cystinosin source, cell (2022). DOI: 10.1016 / j.cell.2022.08.020
University of California – Santa Cruz
the quote: Study Reveals Molecular Origin of Genetic Cystinosis (2022, September 15) Retrieved September 15, 2022 from https://phys.org/news/2022-09-reveals-molecular-genetic-disease-cystinosis.html
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