9I15

Crystal structure of SET cleaved after Asn175 by legumain

9I15 の概要

• エントリーDOI: 10.2210/pdb9i15/pdb
• 分子名称: Isoform 2 of Protein SET, CALCIUM ION (3 entities in total)
• 機能のキーワード: i2pp2a, taf-1, dna binding protein
• 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: 49330.01

構造登録者

Horak, C.,Brandstetter, H.,Dall, E. (登録日: 2025-01-16, 公開日: 2025-07-09)

主引用文献

Horak, C.,Wieland, A.C.,Klaushofer, R.,Briza, P.,Brandstetter, H.,Dall, E.
Conformational and Functional Regulation of SET by Legumain Cleavage.
J.Mol.Biol., 437:169119-169119, 2025

PubMed Abstract: The cysteine protease legumain typically localizes to the endolysosomal system, where it is an important player in the immune system. However, in the context of Alzheimer's disease (AD), legumain has been shown to be translocated to the cytosol, where it cleaves SET, synonymously termed TAF-1 or I2PP2A, an inhibitor of protein phosphatase 2A. SET is primarily found in the nucleus, where it regulates gene transcription, cell cycle progression, and histone acetylation, but can also translocate to the cytoplasm where it regulates cell migration and is implicated in neuronal apoptosis in AD. In this study, we demonstrate that legumain cleaves SET at two major sites: Asn16 at the N-terminal end and Asn175 at the earmuff domain. Contrary to previous findings, our biochemical and crystallographic experiments reveal that the corresponding N- and C-terminal cleavage products remain bound in a stable complex, rather than dissociating. Additionally, we show that the C-terminal acidic stretch of SET is essential for its binding to histone 1, and that cleavage impairs this interaction. Finally, we demonstrate that SET positively modulates PP2A activity. This effect is however abolished upon cleavage by legumain.

PubMed: 40187686
DOI: 10.1016/j.jmb.2025.169119

実験手法

X-RAY DIFFRACTION (2.47 Å)