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

TL;DR

This study investigates the N184K mutation in full-length gelsolin, revealing that it subtly disrupts hydrogen bonding and reduces stability without major structural changes, contributing to understanding amyloidogenic mutations.

Contribution

It provides the first characterization of the full-length N184K gelsolin variant, highlighting its stability issues linked to hydrogen bond network disruption.

Findings

N184K structure similar to wild type in conformation

Thermal stability is reduced in Ca2+-free conditions

Local hydrogen bond network disruption affects stability

Abstract

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.