6FK0
Xray structure of domain-swapped cystatin E dimer
Summary for 6FK0
| Entry DOI | 10.2210/pdb6fk0/pdb |
| Descriptor | Cystatin-M (1 entity in total) |
| Functional Keywords | inhibitor, domain swapping, amyloid fibril, legumain, cathepsin, cysteine protease, hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 29849.86 |
| Authors | Dall, E.,Brandstetter, H. (deposition date: 2018-01-23, release date: 2018-07-11, Last modification date: 2024-10-16) |
| Primary citation | Dall, E.,Hollerweger, J.C.,Dahms, S.O.,Cui, H.,Haussermann, K.,Brandstetter, H. Structural and functional analysis of cystatin E reveals enzymologically relevant dimer and amyloid fibril states. J. Biol. Chem., 293:13151-13165, 2018 Cited by PubMed 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. PubMed: 29967063DOI: 10.1074/jbc.RA118.002154 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.9 Å) |
Structure validation
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