# Calcium-Dependent S100A8 Amyloid Fibril Formation via S100A1-Mediated Transient Interaction

## TL;DR

This study explores how calcium ions influence the interaction and aggregation of S100A1 and S100A8 proteins, which are linked to neurological diseases.

## Contribution

The study reveals calcium-dependent transient interactions between S100A1 and S100A8 that lead to amyloid fibril formation.

## Key findings

- S100A1 and S100A8 interact and coaggregate in a calcium-dependent manner.
- Calcium saturation stabilizes both proteins and inhibits aggregation.
- Transient interactions between S100A1 and S100A8 facilitate worm-like amyloid fibril formation.

## Abstract

The S100 family consists of calcium-binding proteins
that are largely
known for their contribution to neuroinflammatory processes. These
proteins are associated with various cardiac and neurological functions
as well as related diseases. A few S100 proteins can form unspecific
or amyloid aggregates in neuropathologies and thus play a part in
dementia pathogenesis. Among all S100 proteins, S100B and S100A9 aggregation
properties are the most investigated; however, there is a lack of
studies regarding other S100 members. In particular, S100A1 and S100A8
are also associated with neurological pathologies, but their interactions
and aggregation are poorly understood. Therefore, in this study, we
explored whether S100A1 and S100A8 proteins can form heterodimers,
interact, or coaggregate. Our results revealed that S100A1 and S100A8
interactions and S100A8 amyloid aggregation are driven by calcium
ions. We observed that while S100A1 remains mostly stable, S100A8
forms various types of spherical or unspecific aggregates. While they
do not form stable heterodimers like calprotectin, their transient
interactions facilitate the formation of worm-like amyloid fibrils,
and the process is regulated by different calcium ion concentrations.
At calcium ion saturation, both proteins are stabilized, leading to
inhibition of aggregation. Overall, by employing a diverse range of
techniques from amyloid and protein-specific fluorescence detection
to electron–electron double resonance spectroscopy, we elucidated
interactions between S100 proteins that might otherwise be overlooked,
enhancing our understanding of their aggregation behavior.