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Crystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair

Author

Listed:
  • Rebecca Ebenhoch

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Abbas Akhdar

    (Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School)

  • Marc R. Reboll

    (Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School)

  • Mortimer Korf-Klingebiel

    (Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School)

  • Priyanka Gupta

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • Julie Armstrong

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • Yining Huang

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • Lee Frego

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • Irina Rybina

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • John Miglietta

    (Boehringer Ingelheim Pharmaceuticals, Inc.)

  • Anton Pekcec

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

  • Kai C. Wollert

    (Division of Molecular and Translational Cardiology, Department of Cardiology and Angiology, Hannover Medical School)

  • Herbert Nar

    (Boehringer Ingelheim Pharma GmbH & Co. KG)

Abstract

Myeloid-derived growth factor (MYDGF) is a paracrine-acting protein that is produced by bone marrow-derived monocytes and macrophages to protect and repair the heart after myocardial infarction (MI). This effect can be used for the development of protein-based therapies for ischemic tissue repair, also beyond the sole application in heart tissue. Here, we report the X-ray structure of MYDGF and identify its functionally relevant receptor binding epitope. MYDGF consists of a 10-stranded β-sandwich with a folding topology showing no similarities to other cytokines or growth factors. By characterizing the epitope of a neutralizing antibody and utilizing functional assays to study the activity of surface patch-mutations, we were able to localize the receptor interaction interface to a region around two surface tyrosine residues 71 and 73 and an adjacent prominent loop structure of residues 97–101. These findings enable structure-guided protein engineering to develop modified MYDGF variants with potentially improved properties for clinical use.

Suggested Citation

  • Rebecca Ebenhoch & Abbas Akhdar & Marc R. Reboll & Mortimer Korf-Klingebiel & Priyanka Gupta & Julie Armstrong & Yining Huang & Lee Frego & Irina Rybina & John Miglietta & Anton Pekcec & Kai C. Woller, 2019. "Crystal structure and receptor-interacting residues of MYDGF — a protein mediating ischemic tissue repair," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13343-7
    DOI: 10.1038/s41467-019-13343-7
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    Cited by:

    1. Linda Große-Segerath & Paula Follert & Kristina Behnke & Julia Ettich & Tobias Buschmann & Philip Kirschner & Sonja Hartwig & Stefan Lehr & Mortimer Korf-Klingebiel & Daniel Eberhard & Nadja Lehwald-T, 2024. "Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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