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Loss of a metal-binding site in gelsolin leads to familial amyloidosis–Finnish type

Nature Structural Biology volume 9, pages 112–116 (2002)Cite this article

Abstract

Mutations in domain 2 (D2, residues 151–266) of the actin-binding protein gelsolin cause familial amyloidosis–Finnish type (FAF). These mutations, D187N or D187Y, lead to abnormal proteolysis of plasma gelsolin at residues 172–173 and a second hydrolysis at residue 243, resulting in an amyloidogenic fragment. Here we present the structure of human gelsolin D2 at 1.65 Å and find that Asp 187 is part of a Cd2+ metal-binding site. Two Ca2+ ions are required for a conformational transition of gelsolin to its active form. Differential scanning calorimetry (DSC) and molecular dynamics (MD) simulations suggest that the Cd2+-binding site in D2 is one of these two Ca2+-binding sites and is essential to the stability of D2. Mutation of Asp 187 to Asn disrupts Ca2+ binding in D2, leading to instabilities upon Ca2+ activation. These instabilities make the domain a target for aberrant proteolysis, thereby enacting the first step in the cascade leading to FAF.

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Figure 1: The crystal structure of human gelsolin D2 (residues 159–261 shown).
Figure 2: Time course of the wild type and D187N mutant simulations.
Figure 3: More specific interactions contributing to alterations in structure and dynamics at the aberrant clip site.

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Acknowledgements

We thank M. Bycroft for helpful discussions, advice and reviewing the manuscript. We thank A.G. Weeds and B.J. Pope (MRC Laboratory of Molecular Biology, Cambridge, UK) for helpful discussions and advice. S.L.K. was funded by a Hitchings-Elion Fellowship from the Burroughs-Wellcome Fund. Support for the computational studies was provided by the National Institutes of Health.

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Author notes

  1. Steven L. Kazmirski

    Present address: Department of Molecular and Cell Biology, University of California, Berkeley, 401 Barker MC 3202, Berkeley, California, 94720-3202, USA

  2. Rivka L. Isaacson

    Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney St., Boston, Massachusetts, 02115, USA

Authors and Affiliations

  1. Cambridge University Chemical Laboratory and Cambridge Centre for Protein Engineering, MRC Centre, Hills Road, Cambridge, CB2 2QH, UK

    Steven L. Kazmirski, Rivka L. Isaacson, Ashley Buckle, Christopher M. Johnson & Alan R. Fersht

  2. Department of Medicinal Chemistry, University of Washington, Seattle, 98195-7610, Washington, USA

    Chahm An & Valerie Daggett

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Correspondence to Alan R. Fersht.

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Kazmirski, S., Isaacson, R., An, C. et al. Loss of a metal-binding site in gelsolin leads to familial amyloidosis–Finnish type. Nat Struct Mol Biol 9, 112–116 (2002). https://doi.org/10.1038/nsb745

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