  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, 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.
