| Structural highlights
Disease
PAPP2_HUMAN The disease is caused by variants affecting the gene represented in this entry.
Function
PAPP2_HUMAN Metalloproteinase which specifically cleaves insulin-like growth factor binding protein (IGFBP)-5 at the '163-Ser-|-Lys-164' bond. Shows limited proteolysis toward IGFBP-3.[1] [2]
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.
References
- ↑ Overgaard MT, Boldt HB, Laursen LS, Sottrup-Jensen L, Conover CA, Oxvig C. Pregnancy-associated plasma protein-A2 (PAPP-A2), a novel insulin-like growth factor-binding protein-5 proteinase. J Biol Chem. 2001 Jun 15;276(24):21849-53. PMID:11264294 doi:10.1074/jbc.M102191200
- ↑ Dauber A, Muñoz-Calvo MT, Barrios V, Domené HM, Kloverpris S, Serra-Juhé C, Desikan V, Pozo J, Muzumdar R, Martos-Moreno GÁ, Hawkins F, Jasper HG, Conover CA, Frystyk J, Yakar S, Hwa V, Chowen JA, Oxvig C, Rosenfeld RG, Pérez-Jurado LA, Argente J. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016 Apr 1;8(4):363-74. PMID:26902202 doi:10.15252/emmm.201506106
- ↑ Sridar J, Mafi A, Judge RA, Xu J, Kong KA, Wang JCK, Stoll VS, Koukos G, Simon RJ, Eaton D, Bratkowski M, Hao Q. Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition. Commun Chem. 2023 Oct 28;6(1):234. PMID:37898658 doi:10.1038/s42004-023-01032-y
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