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Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism

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Standard

Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. / Kobberø, Sara Dam; Gajhede, Michael; Mirza, Osman Asghar et al.
I: Nature Communications, Bind 13, Nr. 1, 6084, 12.2022.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Harvard

Kobberø, SD, Gajhede, M, Mirza, OA, Kløverpris, S, Kjær, TR, Mikkelsen, JH, Boesen, T & Oxvig, C 2022, 'Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism', Nature Communications, bind 13, nr. 1, 6084. https://doi.org/10.1038/s41467-022-33698-8

APA

Kobberø, S. D., Gajhede, M., Mirza, O. A., Kløverpris, S., Kjær, T. R., Mikkelsen, J. H., Boesen, T., & Oxvig, C. (2022). Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nature Communications, 13(1), artikel 6084. https://doi.org/10.1038/s41467-022-33698-8

CBE

Kobberø SD, Gajhede M, Mirza OA, Kløverpris S, Kjær TR, Mikkelsen JH, Boesen T, Oxvig C. 2022. Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nature Communications. 13(1):Article 6084. https://doi.org/10.1038/s41467-022-33698-8

MLA

Kobberø, Sara Dam et al. "Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism". Nature Communications. 2022. 13(1). https://doi.org/10.1038/s41467-022-33698-8

Vancouver

Kobberø SD, Gajhede M, Mirza OA, Kløverpris S, Kjær TR, Mikkelsen JH et al. Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. Nature Communications. 2022 dec.;13(1):6084. doi: 10.1038/s41467-022-33698-8

Author

Kobberø, Sara Dam ; Gajhede, Michael ; Mirza, Osman Asghar et al. / Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism. I: Nature Communications. 2022 ; Bind 13, Nr. 1.

Bibtex

@article{716e5a0264164bd0a85b67642fdfa1cd,
title = "Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism",
abstract = "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 {\AA}) 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.",
author = "Kobber{\o}, {Sara Dam} and Michael Gajhede and Mirza, {Osman Asghar} and S{\o}ren Kl{\o}verpris and Kj{\ae}r, {Troels R{\o}nn} and Mikkelsen, {Jakob Hauge} and Thomas Boesen and Claus Oxvig",
note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2022",
month = dec,
doi = "10.1038/s41467-022-33698-8",
language = "English",
volume = "13",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

TY - JOUR

T1 - Structure of the proteolytic enzyme PAPP-A with the endogenous inhibitor stanniocalcin-2 reveals its inhibitory mechanism

AU - Kobberø, Sara Dam

AU - Gajhede, Michael

AU - Mirza, Osman Asghar

AU - Kløverpris, Søren

AU - Kjær, Troels Rønn

AU - Mikkelsen, Jakob Hauge

AU - Boesen, Thomas

AU - Oxvig, Claus

N1 - Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85140055713&partnerID=8YFLogxK

U2 - 10.1038/s41467-022-33698-8

DO - 10.1038/s41467-022-33698-8

M3 - Journal article

C2 - 36257932

AN - SCOPUS:85140055713

VL - 13

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 6084

ER -