8SL1

Cryo-EM structure of PAPP-A2

8SL1 の概要

• エントリーDOI: 10.2210/pdb8sl1/pdb
• EMDBエントリー: 40571
• 分子名称: Pappalysin-2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ZINC ION, ... (6 entities in total)
• 機能のキーワード: protease, zinc binding, growth factor signaling, peptide binding, hydrolase, peptide binding protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 175050.94

構造登録者

Judge, R.A.,Stoll, V.S.,Eaton, D.,Hao, Q.,Bratkowski, M.A. (登録日: 2023-04-20, 公開日: 2023-11-08, 最終更新日: 2025-05-14)

主引用文献

Sridar, J.,Mafi, A.,Judge, R.A.,Xu, J.,Kong, K.A.,Wang, J.C.K.,Stoll, V.S.,Koukos, G.,Simon, R.J.,Eaton, D.,Bratkowski, M.,Hao, Q.
Cryo-EM structure of human PAPP-A2 and mechanism of substrate recognition.
Commun Chem, 6:234-234, 2023

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 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.

PubMed: 37898658
DOI: 10.1038/s42004-023-01032-y

実験手法

ELECTRON MICROSCOPY (3.13 Å)