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-Structure paper
Title | Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition. |
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Journal, issue, pages | Commun Chem, Vol. 6, Issue 1, Page 234, Year 2023 |
Publish date | Oct 28, 2023 |
Authors | Janani Sridar / Amirhossein Mafi / Russell A Judge / Jun Xu / Kailyn A Kong / John C K Wang / Vincent S Stoll / Georgios Koukos / Reyna J Simon / Dan Eaton / Matthew Bratkowski / Qi Hao / |
PubMed Abstract | Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor ...Pregnancy-Associated Plasma Protein A isoforms, PAPP-A and PAPP-A2, are metalloproteases that cleave insulin-like growth factor binding proteins (IGFBPs) to modulate insulin-like growth factor signaling. The structures of homodimeric PAPP-A in complex with IGFBP5 anchor peptide, and inhibitor proteins STC2 and proMBP have been recently reported. Here, we present the single-particle cryo-EM structure of the monomeric, N-terminal LG, MP, and the M1 domains (with the exception of LNR1/2) of human PAPP-A2 to 3.13 Å resolution. Our structure together with functional studies provides insight into a previously reported patient mutation that inactivates PAPP-A2 in a distal region of the protein. Using a combinational approach, we suggest that PAPP-A2 recognizes IGFBP5 in a similar manner as PAPP-A and show that PAPP-A2 cleaves IGFBP5 less efficiently due to differences in the M2 domain. Overall, our studies characterize the cleavage mechanism of IGFBP5 by PAPP-A2 and shed light onto key differences with its paralog PAPP-A. |
External links | Commun Chem / PubMed:37898658 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.13 Å |
Structure data | EMDB-40571, PDB-8sl1: |
Chemicals | ChemComp-ZN: ChemComp-NAG: ChemComp-CA: ChemComp-HOH: |
Source |
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Keywords | HYDROLASE / PEPTIDE BINDING PROTEIN / Protease / zinc binding / growth factor signaling / peptide binding |