6FK0

Xray structure of domain-swapped cystatin E dimer

6FK0 の概要

• エントリーDOI: 10.2210/pdb6fk0/pdb
• 分子名称: Cystatin-M (1 entity in total)
• 機能のキーワード: inhibitor, domain swapping, amyloid fibril, legumain, cathepsin, cysteine protease, hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 29849.86

構造登録者

Dall, E.,Brandstetter, H. (登録日: 2018-01-23, 公開日: 2018-07-11, 最終更新日: 2024-10-16)

主引用文献

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

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: 29967063
DOI: 10.1074/jbc.RA118.002154

実験手法

X-RAY DIFFRACTION (2.9 Å)