Scientific Reports (Jan 2021)

Complex of human Melanotransferrin and SC57.32 Fab fragment reveals novel interdomain arrangement with ferric N-lobe and open C-lobe

  • Kristyn Hayashi,
  • Kenton L. Longenecker,
  • Yi-Liang Liu,
  • Bryan Faust,
  • Aditi Prashar,
  • Johannes Hampl,
  • Vincent Stoll,
  • Sandro Vivona

DOI
https://doi.org/10.1038/s41598-020-79090-8
Journal volume & issue
Vol. 11, no. 1
pp. 1 – 9

Abstract

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Abstract Melanotransferrin (MTf) is an iron-binding member of the transferrin superfamily that can be membrane-anchored or secreted in serum. On cells, it can mediate transferrin-independent iron uptake and promote proliferation. In serum, it is a transcytotic iron transporter across the blood–brain barrier. MTf has been exploited as a drug delivery carrier to the brain and as an antibody-drug conjugate (ADC) target due to its oncogenic role in melanoma and its elevated expression in triple-negative breast cancer (TNBC). For treatment of TNBC, an MTf-targeting ADC completed a phase I clinical trial (NCT03316794). The structure of its murine, unconjugated Fab fragment (SC57.32) is revealed here in complex with MTf. The MTf N-lobe is in an active and iron-bound, closed conformation while the C-lobe is in an open conformation incompatible with iron binding. This combination of active and inactive domains displays a novel inter-domain arrangement in which the C2 subdomain angles away from the N-lobe. The C2 subdomain also contains the SC57.32 glyco-epitope, which comprises ten protein residues and two N-acetylglucosamines. Our report reveals novel features of MTf and provides a point of reference for MTf-targeting, structure-guided drug design.