Complex of Human Melanotransferrin and SC57.32 Fab Fragment Reveals Novel Interdomain Arrangement with Ferric N-lobe and Open C-lobe

Overview

Journal Sci Rep

Specialty Science

Date 2021 Jan 13

PMID 33436675

Citations 1

Authors

Kristyn Hayashi

Kenton L Longenecker

Yi-Liang Liu

Bryan Faust

Aditi Prashar

Johannes Hampl

Vincent Stoll

Sandro Vivona

Affiliations

Soon will be listed here.

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.

Citing Articles

Discovery of a Highly Conserved Peptide in the Iron Transporter Melanotransferrin that Traverses an Intact Blood Brain Barrier and Localizes in Neural Cells.

Singh C, Eyford B, Abraham T, Munro L, Choi K, Okon M Front Neurosci. 2021; 15:596976.

PMID: 34149342 PMC: 8212695. DOI: 10.3389/fnins.2021.596976.

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