8sl1: Difference between revisions

Latest revision as of 14:52, 6 November 2024

Cryo-EM structure of PAPP-A2

Structural highlights

8sl1 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.13Å
Ligands:	CA, NAG, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8sl1 is ON HOLD
+==Cryo-EM structure of PAPP-A2==
+<StructureSection load='8sl1' size='340' side='right'caption='[[8sl1]], [[Resolution|resolution]] 3.13&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[8sl1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8SL1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8SL1 FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.13&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8sl1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8sl1 OCA], [https://pdbe.org/8sl1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8sl1 RCSB], [https://www.ebi.ac.uk/pdbsum/8sl1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8sl1 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/PAPP2_HUMAN PAPP2_HUMAN] The disease is caused by variants affecting the gene represented in this entry.
+== Function ==
+[https://www.uniprot.org/uniprot/PAPP2_HUMAN 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.<ref>PMID:11264294</ref> <ref>PMID:26902202</ref>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors:
+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<ref>PMID:37898658</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8sl1" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Bratkowski MA]]
+[[Category: Eaton D]]
+[[Category: Hao Q]]
+[[Category: Judge RA]]
+[[Category: Stoll VS]]

8sl1: Difference between revisions

Latest revision as of 14:52, 6 November 2024

Cryo-EM structure of PAPP-A2

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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