ArticleProceedings of the National Academy of Sciences of the United States of America2016
Cellular folding pathway of a metastable serpin.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 35 citations in OpenAlex.
- From Rat Tails to Glycoproteostasis: Motivated by Biology, Enabled by Biophysics, and Lucky.Journal of molecular biology · 2025Review
- SERPINC1 c.1247dupC: a novel SERPINC1 gene mutation associated with familial thrombosis results in a secretion defect and quantitative antithrombin deficiency.Thrombosis journal · 2024Article
- A tick saliva serpin, IxsS17 inhibits host innate immune system proteases and enhances host colonization by Lyme disease agent.PLoS pathogens · 2024Article
- ER chaperones use a protein folding and quality control glyco-code.Molecular cell · 2023Article
- Co-translational formation of disulfides guides folding of the SARS-CoV-2 receptor binding domain.Biophysical journal · 2023Article
- The conformational landscape of a serpin N-terminal subdomain facilitates folding and in-cell quality control.bioRxiv : the preprint server for biology · 2023Article
- Identification and characterization of two SERPINC1 mutations causing congenital antithrombin deficiency.Thrombosis journal · 2023Article
- Full-length antithrombin frameshift variant with aberrant C-terminus causes endoplasmic reticulum retention with a dominant-negative effect.JCI insight · 2022Article
- Anticoagulant SERPINs: Endogenous Regulators of Hemostasis and Thrombosis.Frontiers in cardiovascular medicine · 2022Review
- Pathways Linking Nicotinamide Adenine Dinucleotide Phosphate Production to Endoplasmic Reticulum Protein Oxidation and Stress.Frontiers in molecular biosciences · 2022Review
- Nascent chains can form co-translational folding intermediates that promote post-translational folding outcomes in a disease-causing protein.Nature communications · 2021Article
- Serpin neuropathology in the P497S UBQLN2 mouse model of ALS/FTD.Brain pathology (Zurich, Switzerland) · 2021Article
- Revisiting the Formation of a Native Disulfide Bond: Consequences for Protein Regeneration and Beyond.Molecules (Basel, Switzerland) · 2020Review
- The metastable states of proteins.Protein science : a publication of the Protein Society · 2020Review
- Proper secretion of the serpin antithrombin relies strictly on thiol-dependent quality control.The Journal of biological chemistry · 2019Article
- Protein Quality Control in the Endoplasmic Reticulum.The protein journal · 2019Review
- All-Atom Simulations Reveal How Single-Point Mutations Promote Serpin Misfolding.Biophysical journal · 2018Article
- On the folding of a structurally complex protein to its metastable active state.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Chemistry and Enzymology of Disulfide Cross-Linking in Proteins.Chemical reviews · 2018Review
- Transient desialylation in combination with a novel antithrombin deficiency causing a severe and recurrent thrombosis despite anticoagulation therapy.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Although proteins generally fold to their thermodynamically most stable state, some metastable proteins populate higher free energy states. Conformational changes from metastable higher free energy states to lower free energy states with greater stability can then generate the work required to perform physiologically important functions. However, how metastable proteins fold to these higher free energy states in the cell and avoid more stable but inactive conformations is poorly understood. The serpin family of metastable protease inhibitors uses large conformational changes that are downhill in free energy to inhibit target proteases by pulling apart the protease active site. The serpin antithrombin III (ATIII) targets thrombin and other proteases involved in blood coagulation, and ATIII misfolding can thus lead to thrombosis and other diseases. ATIII has three disulfide bonds, two near the N terminus and one near the C terminus. Our studies of ATIII in-cell folding reveal a surprising, biased order of disulfide bond formation, with early formation of the C-terminal disulfide, before formation of the N-terminal disulfides, critical for folding to the active, metastable state. Early folding of the predominantly β-sheet ATIII domain in this two-domain protein constrains the reactive center loop (RCL), which contains the protease-binding site, ensuring that the RCL remains accessible. N-linked glycans and carbohydrate-binding molecular chaperones contribute to the efficient folding and secretion of functional ATIII. The inability of a number of disease-associated ATIII variants to navigate the folding reaction helps to explain their disease phenotypes.
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