ジャーナル: Nat Commun / 年: 2022 タイトル: Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. 著者: Sara Dam Kobberø / Michael Gajhede / Osman Asghar Mirza / Søren Kløverpris / Troels Rønn Kjær / Jakob Hauge Mikkelsen / Thomas Boesen / Claus Oxvig / 要旨: The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single- ...The metzincin metalloproteinase PAPP-A plays a key role in the regulation of insulin-like growth factor (IGF) signaling by specific cleavage of inhibitory IGF binding proteins (IGFBPs). Using single-particle cryo-electron microscopy (cryo-EM), we here report the structure of PAPP-A in complex with its endogenous inhibitor, stanniocalcin-2 (STC2), neither of which have been reported before. The highest resolution (3.1 Å) was obtained for the STC2 subunit and the N-terminal approximately 1000 residues of the PAPP-A subunit. The 500 kDa 2:2 PAPP-A·STC2 complex is a flexible multidomain ensemble with numerous interdomain contacts. In particular, a specific disulfide bond between the subunits of STC2 and PAPP-A prevents dissociation, and interactions between STC2 and a module located in the very C-terminal end of the PAPP-A subunit prevent binding of its main substrate, IGFBP-4. While devoid of activity towards IGFBP-4, the active site cleft of the catalytic domain is accessible in the inhibited PAPP-A·STC2 complex, as shown by its ability to hydrolyze a synthetic peptide derived from IGFBP-4. Relevant to multiple human pathologies, this unusual mechanism of proteolytic inhibition may support the development of specific pharmaceutical agents, by which IGF signaling can be indirectly modulated.
全体 : PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
全体
名称: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
要素
複合体: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
複合体: Pregnancy-associated plasma protein A
タンパク質・ペプチド: Pappalysin-1
複合体: Stanniocalcin-2
タンパク質・ペプチド: Stanniocalcin-2
リガンド: ZINC ION
リガンド: CALCIUM ION
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超分子 #1: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer
超分子
名称: PAPP-A dimer in complex with its endogenous inhibitor STC2 dimer タイプ: complex / キメラ: Yes / ID: 1 / 親要素: 0 / 含まれる分子: #1-#2 詳細: Inhibited proteolytic complex generated by harvest of serum media, purifying on a nickel column followed by negative affinity purification and size-exclusion chromatography.
由来(天然)
生物種: Homo sapiens (ヒト) / 組織: ubiquitous / 細胞中の位置: extracellular