The Peptide-binding Cavity Is Essential for Als3-mediated Adhesion of Candida albicans to Human Cells

Lin, Jing; Oh, Soo Hee; Jones, Rhian; Garnett, James A.; Salgado, Paula S.; Rusnakova, Sophia; Matthews, Stephen; Hoyer, Lois L.; Cota, Ernesto

doi:10.1074/jbc.m114.547877

Cited by 70 publications

(141 citation statements)

References 39 publications

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“…Recent work describing the crystal structure of the Nterminal region of Als3 (Lin et al, 2014) has suggested the presence of a PBC that accommodates the C-terminal amino acid residues of polypeptides, thus mediating protein-protein interactions. It is proposed that differences in Als3 specificity for various substrates might be due to variations in C-terminal peptide sequences that can be accommodated in the PBC.…”

Section: Discussionmentioning

confidence: 99%

“…The PBC is formed and covered by a loop from domain N1, providing broad specificity for peptide binding. Amino acid residues in the mature protein between aa 166-172 and 294-298 have side-chains that are in close proximity to ligand within the PBC (Lin et al, 2014). All N-terminal deletions in Als3 spanning 166-305 residues resulted in major inhibitory effects upon Strep.…”

Section: Albicans Als3 Functional Regionsmentioning

confidence: 99%

“…Moreover, the SspB adhesin is covalently anchored to bacterial cell wall peptidoglycan via the C terminus, so there would theoretically be no C-terminal peptide ligand available. It seems more likely that interaction of SspB with Als3 occurs independently of the PBC mechanism proposed for interaction of Als3 with human epithelial cells (Lin et al, 2014). There is also the possibility that force-induced unfolding of the N-terminal domain, resulting from mechanical contact with cells or surfaces, exposes cryptic sequences involved in this protein-protein interaction (Alsteens et al, 2010;Beaussart et al, 2012;Dutton et al, 2014).…”

Section: Albicans Als3 Functional Regionsmentioning

confidence: 99%

“…At the boundary of the Ig-like domain and conserved Thr-rich region is an amyloid-forming region (AFR) (Fig. 1a) that is implicated in cell-cell aggregation and adhesin clustering (Garcia et al, 2011;Beaussart et al, 2012), but may not be involved directly in C. albicans adherence to buccal epithelial cells (Lin et al, 2014). The CRD is believed to enhance the presentation of the adhesive N-terminal region away from the cell surface (Rauceo et al, 2006;Frank et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…The N-terminal domain is predicted to form two Ig folds (Phan et al, 2007) with a peptide-binding cavity (PBC) for interaction with potential substrates, such as the flexible C-termini of polypeptides (Salgado et al, 2011;Lin et al, 2014). At the boundary of the Ig-like domain and conserved Thr-rich region is an amyloid-forming region (AFR) (Fig.…”

Section: Introductionmentioning

confidence: 99%

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Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii

et al. 2015

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The opportunistic pathogen Candida albicans colonizes the oral cavity and gastrointestinal tract. Adherence to host cells, extracellular matrix and salivary glycoproteins that coat oral surfaces, including prostheses, is an important prerequisite for colonization. In addition, interactions of C. albicans with commensal oral streptococci are suggested to promote retention and persistence of fungal cells in mixed-species communities. The hyphal filament specific cell wall protein Als3, a member of the Als protein family, is a major determinant in C. albicans adherence. Here, we utilized site-specific in-frame deletions within Als3 expressed on the surface of heterologous Saccharomyces cerevisiae to determine regions involved in interactions of Als3 with Streptococcus gordonii. N-terminal region amino acid residue deletions D166-225, D218-285, D270-305 and D277-286 were each effective in inhibiting binding of Strep. gordonii to Als3. In addition, these deletions differentially affected biofilm formation, hydrophobicity, and adherence to silicone and human tissue proteins. Deletion of the central repeat domain (D434-830) did not significantly affect interaction of Als3 with Strep. gordonii SspB protein, but affected other adherence properties and biofilm formation. Deletion of the amyloid-forming region (D325-331) did not affect interaction of Als3 with Strep. gordonii SspB adhesin, suggesting this interaction was amyloid-independent. These findings highlighted the essential function of the N-terminal domain of Als3 in mediating the interaction of C. albicans with S. gordonii, and suggested that amyloid formation is not essential for the inter-kingdom interaction.

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Section: Discussionmentioning

confidence: 99%

Section: Albicans Als3 Functional Regionsmentioning

confidence: 99%

Section: Albicans Als3 Functional Regionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii

et al. 2015

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Candida parapsilosis cell wall proteins—CPAR2_404800 and CPAR2_404780—Are adhesins that bind to human epithelial and endothelial cells and extracellular matrix proteins

Satała

Karkowska‐Kuleta

Bras

et al. 2023

Yeast

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One of the initial steps necessary for the development of Candida infections is the adherence to the host tissues and cells. Recent transcriptomic studies suggest that, in Candida parapsilosis—a fungal infectious agent that causes systemic candidiasis in immunosuppressed individuals—the adhesion is mediated by pathogen cell‐exposed proteins belonging to the agglutinin‐like sequence (Als) family. However, to date, the actual interactions of individual members of this family with human cells and extracellular matrix (ECM) have not been characterized in detail. In the current study, we focused attention on two of these C. parapsilosis Als proteins—CPAR2_404800 and CPAR2_404780—that were proteomically identified in the fungal cell wall of yeasts grown in the media suitable for culturing human epithelial and endothelial cells. Both proteins were extracted from the cell wall and purified, and using a microplate binding assay and a fluorescence microscopic analysis were shown to adhere to human cells of A431 (epithelial) and HMEC‐1 (endothelial) lines. The human extracellular matrix components that are also plasma proteins—fibronectin and vitronectin—enhanced these interactions, and also could directly bind to CPAR2_404800 and CPAR2_404780 proteins, with a high affinity (KD in a range of 10−7 to 10−8 M) as determined by surface plasmon resonance measurements. Our findings highlight the role of proteins CPAR2_404800 and CPAR2_404780 in adhesion to host cells and proteins, contributing to the knowledge of the mechanisms of host‐pathogen interactions during C. parapsilosis‐caused infections.

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Antifungal Efficacy of Terpenes and Mechanism of Action Against Human Pathogenic Fungi

Raj,

Parveen,

Khatoon

et al. 2024

Advances in Antifungal Drug Development

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The Peptide-binding Cavity Is Essential for Als3-mediated Adhesion of Candida albicans to Human Cells

Cited by 70 publications

References 39 publications

Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii

Functional regions of Candida albicans hyphal cell wall protein Als3 that determine interaction with the oral bacterium Streptococcus gordonii

Candida parapsilosis cell wall proteins—CPAR2_404800 and CPAR2_404780—Are adhesins that bind to human epithelial and endothelial cells and extracellular matrix proteins

Antifungal Efficacy of Terpenes and Mechanism of Action Against Human Pathogenic Fungi

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