9CHY

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

Summary for 9CHY

• Entry DOI: 10.2210/pdb9chy/pdb
• Descriptor: Guanosine-3',5'-bis(diphosphate) 3'-pyrophosphohydrolase MESH1, ZINC ION, 3'-PHOSPHATE-ADENOSINE-5'-PHOSPHATE SULFATE, ... (6 entities in total)
• Functional Keywords: phosphatase, paps, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 42296.03

Authors

Rose, J.,Zhou, P. (deposition date: 2024-07-02, release date: 2025-12-10, Last modification date: 2026-04-22)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.9 Å)