6TAV

Crystal structure of endopeptidase-induced alpha2-macroglobulin

Replaces:  4ACQ

Summary for 6TAV

• Entry DOI: 10.2210/pdb6tav/pdb
• Descriptor: Alpha-2-macroglobulin, alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (5 entities in total)
• Functional Keywords: peptidase inhibitor, proteinase inhibitor, zn-and cu-binding protein, cytokine binding, hormone binding, protein binding, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 666202.72

Authors

Gomis-Ruth, F.X.,Duquerroy, S.,Trapani, S.,Marrero, A.,Goulas, T.,Guevara, T.,Andersen, G.A.,Sottrup-Jensen, L.,Navaza, J. (deposition date: 2019-10-30, release date: 2021-05-12, Last modification date: 2025-09-17)

Primary citation

Luque, D.,Goulas, T.,Mata, C.P.,Mendes, S.R.,Gomis-Ruth, F.X.,Caston, J.R.
Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human alpha 2 -macroglobulin.
Proc.Natl.Acad.Sci.USA, 119:e2200102119-e2200102119, 2022

PubMed Abstract: Human α2-macroglobulin (hα2M) is a multidomain protein with a plethora of essential functions, including transport of signaling molecules and endopeptidase inhibition in innate immunity. Here, we dissected the molecular mechanism of the inhibitory function of the ∼720-kDa hα2M tetramer through eight cryo–electron microscopy (cryo-EM) structures of complexes from human plasma. In the native complex, the hα2M subunits are organized in two flexible modules in expanded conformation, which enclose a highly porous cavity in which the proteolytic activity of circulating plasma proteins is tested. Cleavage of bait regions exposed inside the cavity triggers rearrangement to a compact conformation, which closes openings and entraps the prey proteinase. After the expanded-to-compact transition, which occurs independently in the four subunits, the reactive thioester bond triggers covalent linking of the proteinase, and the receptor-binding domain is exposed on the tetramer surface for receptor-mediated clearance from circulation. These results depict the molecular mechanism of a unique suicidal inhibitory trap.

PubMed: 35500114
DOI: 10.1073/pnas.2200102119

Experimental method

X-RAY DIFFRACTION (4.2 Å)