9CHY

Crystal structure of the human MESH1 (D66K)-PAPS complex

9CHY の概要

• エントリーDOI: 10.2210/pdb9chy/pdb
• 分子名称: Guanosine-3',5'-bis(diphosphate) 3'-pyrophosphohydrolase MESH1, ZINC ION, 3'-PHOSPHATE-ADENOSINE-5'-PHOSPHATE SULFATE, ... (6 entities in total)
• 機能のキーワード: phosphatase, paps, hydrolase
• 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: 42296.03

構造登録者

Rose, J.,Zhou, P. (登録日: 2024-07-02, 公開日: 2025-12-10, 最終更新日: 2026-04-22)

主引用文献

Lin, C.C.,Rose, J.,Zhang, A.,Mirando, A.J.,Mestre, A.A.,Ding, C.C.,Liao, Y.,Chen, S.Y.,Setayeshpour, Y.,Wu, J.,Li, Z.,Yan, D.,Hilton, M.J.,Zhou, P.,Chi, J.T.
MESH1 functions as a metazoan PAPS phosphatase to regulate sulfation.
Nat.Chem.Biol., 2026

PubMed Abstract: Biological sulfation reactions require 3'-phosphoadenosine-5'-phosphosulfate (PAPS) as the universal sulfate donor. While the biosynthetic pathway of PAPS has been well characterized, the phosphatase degrading PAPS remains unidentified. Here, we discover MESH1 as a PAPS phosphatase that hydrolyzes PAPS into adenosine-5'-phosphosulfate and phosphate. Our crystallographic analysis of the MESH1-PAPS complex confirms PAPS as a bona fide substrate of MESH1. We further show that MESH1 localizes to Golgi, where sulfotransferases consume PAPS to produce sulfated glycosaminoglycan (sGAG). We show that MESH1 (also known as HDDC3) knockdown enhances sGAG production in a chondrogenic cell line. Furthermore, in brachymorphic mice, Mesh1 knockout significantly elevates sGAG levels in joint cartilage and improves bone density. In Caenorhabditis elegans lacking bpnt-1, neurotoxic PAP accumulation is alleviated by MESH1 overexpression, reducing upstream PAPS levels. Our biochemical, structural and functional findings establish MESH1 as a key PAPS phosphatase and highlights its potential as a therapeutic target in disorders characterized by sulfation deficiency.

PubMed: 41963701
DOI: 10.1038/s41589-026-02190-5

実験手法

X-RAY DIFFRACTION (1.9 Å)