Article

Structural basis for the broad specificity to host-cell ligands by the pathogenic fungus Candida albicans

Division of Molecular Biosciences, Imperial College London, Exhibition Road, South Kensington SW7 2AZ, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2011; 108(38):15775-9. DOI: 10.1073/pnas.1103496108
Source: PubMed

ABSTRACT Candida albicans is the most prevalent fungal pathogen in humans and a major source of life-threatening nosocomial infections. The Als (agglutinin-like sequence) glycoproteins are an important virulence factor for this fungus and have been associated with binding of host-cell surface proteins and small peptides of random sequence, the formation of biofilms and amyloid fibers. High-resolution structures of N-terminal Als adhesins (NT-Als; up to 314 amino acids) show that ligand recognition relies on a motif capable of binding flexible C termini of peptides in extended conformation. Central to this mechanism is an invariant lysine that recognizes the C-terminal carboxylate of ligands at the end of a deep-binding cavity. In addition to several protein-peptide interactions, a network of water molecules runs parallel to one side of the ligand and contributes to the recognition of diverse peptide sequences. These data establish NT-Als adhesins as a separate family of peptide-binding proteins and an unexpected adhesion system for primary, widespread protein-protein interactions at the Candida/host-cell interface.

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Available from: Paula Salgado, Sep 01, 2015
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    • "This adhesion is mediated by cell wall components that interact with the host cells. The cell wall of C. albicans contains different carbohydrates that come into contact with epithelial cells and facilitate cell–cell interconnections (Klotz et al. 2004; Salgado et al. 2011; Tsai et al. 2011). Between these carbohydrates, mannans are the main and the major antigenic component of the cell wall of yeast (Nelson et al. 1991; Tsai et al. 2011; Hardison and Brown 2012). "
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    • "These Ig-fold domains bind to many different peptide sequences, either as soluble peptides or as unstructured parts of proteins [4] [5] [6]. The structures of these domains have now been determined [7]. Following the Ig-like domains is a Thr-rich domain of 108 amino acids, called the T domain. "
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    • "Among the adhesins, the Agglutinin-like sequence (Als) family includes cell wall-linked glycoproteins encoded at 8 loci [29], [30]. Each member of the Als family contain N-terminal Ig-like invasin domains (Ig) which define substrate specificity and a variable number of 36-amino acid tandem repeats (TR domain) that contribute to substrate binding [31]–[34]. There is a glycosylated serine-threonine–rich domain and a GPI anchor that covalently links the protein to the cell [35]. "
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