8sl1

Publication Abstract from PubMed

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 A 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.

Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.,Sridar J, Mafi A, Judge RA, Xu J, Kong KA, Wang JCK, Stoll VS, Koukos G, Simon RJ, Eaton D, Bratkowski M, Hao Q Commun Chem. 2023 Oct 28;6(1):234. doi: 10.1038/s42004-023-01032-y. PMID:37898658^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.