The structure of N184K amyloidogenic variant of gelsolin highlights the role of the H-bond network for protein stability and aggregation properties

  • Matteo de RosaEmail author
  • Alberto Barbiroli
  • Francesco Bonì
  • Emanuele Scalone
  • Davide Mattioni
  • Maria A. Vanoni
  • Marco Patrone
  • Michela Bollati
  • Eloise Mastrangelo
  • Toni Giorgino
  • Mario Milani
Original Article


Mutations in the gelsolin protein are responsible for a rare conformational disease known as AGel amyloidosis. Four of these mutations are hosted by the second domain of the protein (G2): D187N/Y, G167R and N184K. The impact of the latter has been so far evaluated only by studies on the isolated G2. Here we report the characterization of full-length gelsolin carrying the N184K mutation and compare the findings with those obtained on the wild type and the other variants. The crystallographic structure of the N184K variant in the Ca2+-free conformation shows remarkable similarities with the wild type protein. Only minimal local rearrangements can be observed and the mutant is as efficient as the wild type in severing filamentous actin. However, the thermal stability of the pathological variant is compromised in the Ca2+-free conditions. These data suggest that the N to K substitution causes a local disruption of the H-bond network in the core of the G2 domain. Such a subtle rearrangement of the connections does not lead to significant conformational changes but severely affects the stability of the protein.


Agel amyloidosis Gelsolin X-ray crystallography Thermal stability Misfolding 



This research was supported by a Research Grant of the Amyloidosis Foundation (Michigan, United States) awarded to MdR. The diffraction experiments were performed on beamline ID23-1, ID29 and Massif-3 at the European Synchrotron Radiation Facility (ESRF, France). We are thankful for the provided beamtime and assistance during the measurements.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© European Biophysical Societies' Association 2019

Authors and Affiliations

  1. 1.Istituto di BiofisicaConsiglio Nazionale delle RicercheMilanItaly
  2. 2.Dipartimento di BioscienzeUniversità degli Studi di MilanoMilanItaly
  3. 3.Dipartimento di Scienze per gli Alimenti, la Nutrizione e l’AmbienteUniversità degli Studi di MilanoMilanItaly
  4. 4.Biocrystallography Unit, Division of Immunology, Transplantation and Infectious DiseasesIRCCS San Raffaele Scientific InstituteMilanItaly

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