Structural Bases of the Redox-dependent Conformational Switch in the Serpin PAI-2

Lobov, SergeiUmeå universitet,Institutionen för medicinsk kemi och biofysik (författare)

Depending on the redox-status, the serpin plasminogen activator inhibitor type 2 (PAI-2) can exist in either a stable monomeric or polymerogenic form. The latter form, which spontaneously forms loop-sheet polymers, has an open β-sheet A and is stabilized by a disulfide bond between C79 (in the CD-loop) and C161 (at the bottom of PAI-2). Reduction of this bond results in a closing of the β-sheet A and converts PAI-2 to a stable monomeric form. Here we show that the stable monomeric and polymerogenic forms of PAI-2 are fully interconvertible, depending on redox-status of the environment. Our intramolecular distance measurements indicate that the CD-loop folds mainly on one side of the stable monomeric form of the inhibitor. However, the loop can translocate about 54 Å to the bottom of PAI-2 so that the C79–C161 disulfide bond can form under oxidizing conditions. We show also that the redox-active C79 can form a disulfide-link to the matrix protein vitronectin, suggesting that vitronectin can stabilize active PAI-2 in extracellular compartments. PAI-2 is therefore a rare example of a redox-sensitive protein for which the activity and polymerization ability are regulated by reversible disulfide bond formation leading to major translocation of a loop and significant conformational changes in the molecule.

Wilczynska, MalgorzataUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)mawi0006 (författare)
Bergström, FredrikUmeå universitet,Kemiska institutionen (författare)
Johansson, Lennart B-ÅUmeå universitet,Kemiska institutionen(Swepub:umu)lejo0007 (författare)
Ny, TorUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)tony0001 (författare)
Umeå universitetInstitutionen för medicinsk kemi och biofysik (creator_code:org_t)

Av författaren/redakt...: Lobov, Sergei; Wilczynska, Malg ...; Bergström, Fredr ...; Johansson, Lenna ...; Ny, Tor

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