Sridar Janani, Mafi Amirhossein, Judge Russell A, Xu Jun, Kong Kailyn A, Wang John C K, Stoll Vincent S, Koukos Georgios, Simon Reyna J, Eaton Dan, Bratkowski Matthew, Hao Qi
Calico Life Sciences LLC, South San Francisco, CA, 94080, USA.
AbbVie, 1 North Waukegan Rd, North Chicago, IL, 60064, USA.
Commun Chem. 2023 Oct 28;6(1):234. doi: 10.1038/s42004-023-01032-y.
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.
妊娠相关血浆蛋白A亚型，即PAPP - A和PAPP - A2，是金属蛋白酶，可切割胰岛素样生长因子结合蛋白（IGFBPs）以调节胰岛素样生长因子信号传导。最近报道了与IGFBP5锚定肽、抑制蛋白STC2和前MBP复合的同二聚体PAPP - A的结构。在此，我们展示了人PAPP - A2单体的N端LG、MP和M1结构域（LNR1/2除外）的单颗粒冷冻电镜结构，分辨率达到3.13 Å。我们的结构与功能研究共同揭示了先前报道的一个患者突变，该突变使PAPP - A2在蛋白质的远端区域失活。通过组合方法，我们表明PAPP - A2以与PAPP - A相似的方式识别IGFBP5，并表明由于M2结构域的差异，PAPP - A2切割IGFBP5的效率较低。总体而言，我们的研究表征了PAPP - A2对IGFBP5的切割机制，并揭示了其与旁系同源物PAPP - A的关键差异。
