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TitleStructure of the PAPP-A complex reveals mechanism of substrate recognition.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 5500, Year 2022
Publish dateSep 20, 2022
AuthorsRussell A Judge / Janani Sridar / Kathryn Tunyasuvunakool / Rinku Jain / John C K Wang / Christna Ouch / Jun Xu / Amirhossein Mafi / Aaron H Nile / Clint Remarcik / Corey L Smith / Crystal Ghosh / Chen Xu / Vincent Stoll / John Jumper / Amoolya H Singh / Dan Eaton / Qi Hao /
PubMed AbstractInsulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are ...Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-A) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.
External linksNat Commun / PubMed:36127359 / PubMed Central
MethodsEM (single particle)
Resolution3.28 - 3.35 Å
Structure data

26475

7ufg

EMDB-26475, PDB-7ufg:
Cryo-EM structure of PAPP-A in complex with IGFBP5
Method: EM (single particle) / Resolution: 3.28 Å

27253

8d8o

EMDB-27253, PDB-8d8o:
Cryo-EM structure of substrate unbound PAPP-A
Method: EM (single particle) / Resolution: 3.35 Å

Chemicals

ChemComp-ZN:
Unknown entry

Source
  • homo sapiens (human)
KeywordsHYDROLASE/Hormone / Metalloprotease / Metal-binding / HYDROLASE / HYDROLASE-Hormone complex

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