ArticleThe Journal of biological chemistry2018
Structural and functional analysis of cystatin E reveals enzymologically relevant dimer and amyloid fibril states.
Article in The Journal of biological chemistry, 2018. 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, 30 citations in OpenAlex.
- Review
- Article
- Crystal structure of Echinococcus multilocularis cystatin B reveals a novel feature in classical stefins.Scientific reports · 2026Article
- Identification of maternal antibodies targeting a cystatin-like protein of Trichinella spiralis in offspring.Parasites, hosts and diseases · 2026Article
- Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia.Scientific reports · 2025Article
- Insights into mechanisms and significance of domain swapping from emerging examples in the Mog1p/PsbP-like fold.Biochemical and biophysical research communications · 2025Review
- Correlation of Experimental and Calculated Inhibition Constants of Protease Inhibitor Complexes.International journal of molecular sciences · 2024Article
- Article
- Phytocystatin 6 is a context-dependent, tight-binding inhibitor of Arabidopsis thaliana legumain isoform β.The Plant journal : for cell and molecular biology · 2023Article
- Type 2 Cystatins and Their Roles in the Regulation of Human Immune Response and Cancer Progression.Cancers · 2023Review
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
- Oligomerization of Human Cystatin C-An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies.International journal of molecular sciences · 2022Article
- Structural and functional studies of legumain-mycocypin complexes revealed a competitive, exosite-regulated mode of interaction.The Journal of biological chemistry · 2022Article
- Is amyloid fibrillation related to 3D domain swapping for the C-terminal domain of SARS-CoV main protease?International journal of biological macromolecules · 2022Article
- Review
- Structural and functional studies ofThe Journal of biological chemistry · 2020Article
- The Structural Basis of T4 Phage Lysis Control: DNA as the Signal for Lysis Inhibition.Journal of molecular biology · 2020Article
- Maturation of the functional mouse CRES amyloid from globular form.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- δ-secretase in neurodegenerative diseases: mechanisms, regulators and therapeutic opportunities.Translational neurodegeneration · 2020Review
- A functional enrichment test for molecular convergent evolution finds a clear protein-coding signal in echolocating bats and whales.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein activity is often regulated by altering the oligomerization state. One mechanism of multimerization involves domain swapping, wherein proteins exchange parts of their structures and thereby form long-lived dimers or multimers. Domain swapping has been specifically observed in amyloidogenic proteins, for example the cystatin superfamily of cysteine protease inhibitors. Cystatins are twin-headed inhibitors, simultaneously targeting the lysosomal cathepsins and legumain, with important roles in cancer progression and Alzheimer's disease. Although cystatin E is the most potent legumain inhibitor identified so far, nothing is known about its propensity to oligomerize. In this study, we show that conformational destabilization of cystatin E leads to the formation of a domain-swapped dimer with increased conformational stability. This dimer was active as a legumain inhibitor by forming a trimeric complex. By contrast, the binding sites toward papain-like proteases were buried within the cystatin E dimer. We also showed that the dimers could further convert to amyloid fibrils. Unexpectedly, cystatin E amyloid fibrils contained functional protein, which inhibited both legumain and papain-like enzymes. Fibril formation was further regulated by glycosylation. We speculate that cystatin amyloid fibrils might serve as a binding platform to stabilize the pH-sensitive legumain and cathepsins in the extracellular environment, contributing to their physiological and pathological functions.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.