Details

Autor(en) / Beteiligte

• Luque, Daniel
• Goulas, Theodoros
• Mata, Carlos P
• Mendes, Soraia R
• Gomis-Rüth, F Xavier
• Castón, José R

Titel

Cryo-EM structures show the mechanistic basis of pan-peptidase inhibition by human α 2 -macroglobulin

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2022-05, Vol.119 (19), p.e2200102119

Ort / Verlag

United States

Erscheinungsjahr

2022

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.