Structure of the PAPP-ABP5 complex reveals mechanism of substrate recognition

Russell A. Judge, Janani Sridar, Kathryn Tunyasuvunakool, Rinku Jain, John C. K. Wang, Christna Ouch, Jun Xu, Amirhossein Mafi, Aaron H. Nile, Clint Remarcik, Corey L. Smith, Crystal Ghosh, Chen Xu, Vincent Stoll, John Jumper, Amoolya H. Singh, Dan Eaton () and Qi Hao ()
Additional contact information
Russell A. Judge: AbbVie
Janani Sridar: Calico Life Sciences LLC
Kathryn Tunyasuvunakool: DeepMind
Rinku Jain: AbbVie
John C. K. Wang: Calico Life Sciences LLC
Christna Ouch: University of Massachusetts Chan Medical School
Jun Xu: Calico Life Sciences LLC
Amirhossein Mafi: Calico Life Sciences LLC
Aaron H. Nile: Calico Life Sciences LLC
Clint Remarcik: Calico Life Sciences LLC
Corey L. Smith: AbbVie Bioresearch Center
Crystal Ghosh: Calico Life Sciences LLC
Chen Xu: University of Massachusetts Chan Medical School
Vincent Stoll: AbbVie
John Jumper: DeepMind
Amoolya H. Singh: Calico Life Sciences LLC
Dan Eaton: Calico Life Sciences LLC
Qi Hao: Calico Life Sciences LLC

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Insulin-like growth factor (IGF) signaling is highly conserved and tightly regulated by proteases including Pregnancy-Associated Plasma Protein A (PAPP-A). PAPP-A and its paralog PAPP-A2 are metalloproteases that mediate IGF bioavailability through cleavage of IGF binding proteins (IGFBPs). Here, we present single-particle cryo-EM structures of the catalytically inactive mutant PAPP-A (E483A) in complex with a peptide from its substrate IGFBP5 (PAPP-ABP5) and also in its substrate-free form, by leveraging the power of AlphaFold to generate a high quality predicted model as a starting template. We show that PAPP-A is a flexible trans-dimer that binds IGFBP5 via a 25-amino acid anchor peptide which extends into the metalloprotease active site. This unique IGFBP5 anchor peptide that mediates the specific PAPP-A-IGFBP5 interaction is not found in other PAPP-A substrates. Additionally, we illustrate the critical role of the PAPP-A central domain as it mediates both IGFBP5 recognition and trans-dimerization. We further demonstrate that PAPP-A trans-dimer formation and distal inter-domain interactions are both required for efficient proteolysis of IGFBP4, but dispensable for IGFBP5 cleavage. Together the structural and biochemical studies reveal the mechanism of PAPP-A substrate binding and selectivity.

Date: 2022
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DOI: 10.1038/s41467-022-33175-2

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