9FX2

Structure of methylamine activated CD109

Summary for 9FX2

• Entry DOI: 10.2210/pdb9fx2/pdb
• EMDB information: 50841
• Descriptor: CD109 antigen, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: protease inhibitor, thioester activation, intermediate conformation, alpha-macroglobulin, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 141555.84

Authors

Almeida, A.V.,Andersen, G.R. (deposition date: 2024-07-01, release date: 2025-03-19, Last modification date: 2025-09-17)

Primary citation

Almeida, A.V.,Jensen, K.T.,Harwood, S.L.,Jorgensen, M.H.,Nielsen, N.S.,Thogersen, I.B.,Enghild, J.J.,Andersen, G.R.
Three cryo-EM structures of CD109 reveal its mechanism of protease inhibition.
Cell Rep, 44:115787-115787, 2025

PubMed Abstract: CD109 is a glycosylphosphatidylinositol-anchored protein. In addition to regulating transforming growth factor β (TGF-β) network signaling, CD109 is also a protease inhibitor. Protease cleavage of its bait region triggers a conformational change releasing the major fragment from the cell surface, exposing a reactive thioester that can conjugate proteases. To understand this protease inhibition mechanism, we determined cryoelectron microscopy structures of CD109 in native, protease-activated, and methylamine-activated conformations. Despite CD109's low sequence similarity with the protease inhibitor A2ML1, CD109 adopts a similar protease-activated conformation, suggesting a shared mechanism of protease inhibition. Deglycosylation of CD109 does not affect chymotrypsin conjugation but enhances substrate access, suggesting that CD109 glycans contribute to protease inhibition. Our data provide a structural basis for understanding CD109's protease-triggered membrane release, its protease inhibitory mechanism, and additional biological functions.

PubMed: 40482031
DOI: 10.1016/j.celrep.2025.115787

Experimental method

ELECTRON MICROSCOPY (3.3 Å)