A New Function for Amyloid-Like Interactions: Cross-Beta Aggregates of Adhesins form Cell-to-Cell Bonds

Abstract

Amyloid structures assemble through a repeating type of bonding called “cross-β”, in which identical sequences in many protein molecules form β-sheets that interdigitate through side chain interactions. We review the structural characteristics of such bonds. Single cell force microscopy (SCFM) shows that yeast expressing Als5 adhesin from Candida albicans demonstrate the empirical characteristics of cross-β interactions. These properties include affinity for amyloid-binding dyes, birefringence, critical concentration dependence, repeating structure, and inhibition by anti-amyloid agents. We present a model for how cross-β bonds form in trans between two adhering cells. These characteristics also apply to other fungal adhesins, so the mechanism appears to be an example of a new type of cell–cell adhesion.

FLO11, a Developmental Gene Conferring Impressive Adaptive Plasticity to the Yeast Saccharomyces cerevisiae

“…This data argued that a threshold number of these short β-aggregation prone sequences is necessary for effective nanodomains production under shear force [37]. Moreover, this work provided evidence that amyloid-core sequences contribute to trans-interactions between Flo11p of opposing cells, and hence supported the model of Lipke and colleagues for a dual role of amyloid β-sheet interactions; that is, in the formation of clusters of Flo11p on the cell surface (cis-interaction) and in homophilic bonding between Flo11p of opposing cells (trans-interactions) [66,68]. Taking into account these data and that Flo11p can connect cells by forming an extracellular matrix that involves co-aligned Flo11 fibers as suggested from ultrastructure analysis by electron microscopy [24], we propose the model depicted in Figure 2 in which nanodomains resulting from cis-interactions of Flo11p on the cell surface may enhance the homophilic interactions between Flo11 proteins of opposing cells, strengthening henceforth cell-cell interactions.…”

“…In the pathogenic yeast, Candida albicans, this phenomenon has received a lot of attention because cell surface adhesins control essential processes of adhesion, colonization, and biofilm formation on host tissues and indwelling medical catheters [64]. Work from Lipke and colleagues have shown that these amyloid-core sequences are needed for clustering adhesin molecules in cis on the cell surface, but they also mediate cell-cell interaction in trans through these cross-β bonds [65,66]. The Flo11p from the laboratory strains S288c and Σ1278b has two typical amyloid core sequences (VVSTTV/VTTAVT) at the boundary between the middle region and the C-terminal domain (see Figure 1), which may likely explain that a soluble version of this protein can assemble into amyloid fibers in vitro [28,29].…”

The Flo Adhesin Family

“…As for Flo1p, data on Flo11p also support the involvement of this adhesin in the formation of cross-β bonds in trans between cells [109]. There are potential amyloid core sequences in the post N-terminal domain and C-terminal regions [133].…”

“…These intercellular bonds show properties of cross-β aggregation and in addition to the interactions that cluster the adhesins on yeast cell surfaces [110]. Data on Flo1p also support the formation of cross-β bonds in trans between expressing cells [109]. The N-Flo1p domain is followed by a variable number of tandem repeats that are predicted to have anti-parallel β-sheet structure, and these repeats unfold under extension or shear force [110,111].…”

“…In both steps, Ca 2+ is crucial for the interactions. It has been recently discovered that amyloid-like bonds can contribute to C. albicans cell-cell interactions via the Als adhesins [107][108][109]. These intercellular bonds show properties of cross-β aggregation and in addition to the interactions that cluster the adhesins on yeast cell surfaces [110].…”