Structure and Function of Glycosylated Tandem Repeats from Candida albicans Als Adhesins

Frank, Aaron T.; Ramsook, Caleen B.; Otoo, Henry N.; Tan, Cho; Soybelman, Gregory; Rauceo, Jason M.; Gaur, Nand K.; Klotz, Stephen A.; Lipke, Peter N.

doi:10.1128/ec.00235-09

Cited by 57 publications

(54 citation statements)

References 53 publications

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“…Some genes encoding for proteins with multiple functions, including those affecting the hydrophobic properties of C. albicans, have already been described [3,14]. The protein Csh1, coded by the already cloned and analyzed CSH1 gene, has been hypothesized to affect total CSH status, and to contribute to virulence of C. albicans in mice [3].…”

Section: Resultsmentioning

confidence: 99%

Role of cell surface hydrophobicity in Candida albicans biofilm

et al. 2013

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Section: Resultsmentioning

confidence: 99%

Role of cell surface hydrophobicity in Candida albicans biofilm

et al. 2013

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“…In the initial stage, stretching and unfolding of Als5p with the AFM tip extends conformations in which homologous hydrophobic interactions are favored. Fast hydrophobic interactions between extended tandem repeats would first promote Als5p self-associations and the recruitment of further neighboring proteins (15). Next, slower interactions would take place between the stimulated proteins, such as amyloid interactions between threonine-rich regions, and then propagate across the entire surface.…”

Section: Discussionmentioning

confidence: 99%

“…1A) (13)(14)(15). Previous studies in C. albicans and in a Saccharomyces cerevisiae surface display model showed that Als5p-mediated adhesion involves a rapid cellto-ligand adhesion step, followed by slower cell-to-cell aggregation mediated by the T and TR regions (13,15). These kinetics suggest that, following adhesion to ligands, Als5p may undergo conformational changes that mediate cellular aggregation.…”

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confidence: 97%

“…Als proteins are covalently attached to the cell wall and consist of an N-terminal Ig-like region, which initiates cell adhesion, followed by a threonine-rich region with an amyloid-forming sequence (T), a tandem repeat (TR) region that participates in cellcell aggregation, and a stalk region projecting the molecule away from the cell surface (Fig. 1A) (13)(14)(15). Previous studies in C. albicans and in a Saccharomyces cerevisiae surface display model showed that Als5p-mediated adhesion involves a rapid cellto-ligand adhesion step, followed by slower cell-to-cell aggregation mediated by the T and TR regions (13,15).…”

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confidence: 99%

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Force-induced formation and propagation of adhesion nanodomains in living fungal cells

Alsteens

Garcia

Lipke

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Understanding how cell adhesion proteins form adhesion domains is a key challenge in cell biology. Here, we use single-molecule atomic force microscopy (AFM) to demonstrate the force-induced formation and propagation of adhesion nanodomains in living fungal cells, focusing on the covalently anchored cell-wall protein Als5p from Candida albicans. We show that pulling on single adhesins with AFM tips terminated with specific antibodies triggers the formation of adhesion domains of 100-500 nm and that the forceinduced nanodomains propagate over the entire cell surface. Control experiments (with cells lacking Als5p, single-site mutation in the protein, bare tips, and tips modified with irrelevant antibodies) demonstrate that Als5p nanodomains result from protein redistribution triggered by force-induced conformational changes in the initially probed proteins, rather than from nonspecific cell-wall perturbations. Als5p remodeling is independent of cellular metabolic activity because heat-killed cells show the same behavior as live cells. Using AFM and fluorescence microscopy, we also find that nanodomains are formed within ∼30 min and migrate at a speed of ∼20 nm·min −1 , indicating that domain formation and propagation are slow, time-dependent processes. These results demonstrate that mechanical stimuli can trigger adhesion nanodomains in fungal cells and suggest that the force-induced clustering of adhesins may be a mechanism for activating cell adhesion.single-molecule techniques | microbial adhesion | glycoproteins | fungi C ell adhesion is a ubiquitous feature of living cells and plays essential roles in a variety of cellular processes, including neuronal interactions, cellular communication, inflammation, and microbial infection (1-5). A growing body of evidence indicates that, in mammalian cells, the early stage of adhesion involves the formation of adhesion domains (i.e., focal adhesion complexes) composed of aggregated proteins (6, 7). A remarkable trait of adhesion domains is their ability to grow and strengthen under force (8-10). Whether such force-dependent behavior also occurs with microbial adhesins is unknown.Adhesins in the Candida albicans Als gene family bind the pathogen to host tissues and initiate biofilm formation (11,12). Als proteins are covalently attached to the cell wall and consist of an N-terminal Ig-like region, which initiates cell adhesion, followed by a threonine-rich region with an amyloid-forming sequence (T), a tandem repeat (TR) region that participates in cellcell aggregation, and a stalk region projecting the molecule away from the cell surface (Fig. 1A) (13-15). Previous studies in C. albicans and in a Saccharomyces cerevisiae surface display model showed that Als5p-mediated adhesion involves a rapid cellto-ligand adhesion step, followed by slower cell-to-cell aggregation mediated by the T and TR regions (13, 15). These kinetics suggest that, following adhesion to ligands, Als5p may undergo conformational changes that mediate cellular aggregation. Consistent with this, Rauceo ...

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“…These repeats are rich in serine and threonine, exposed on the cell surface, and required for adherence function (31,49). Because they are hydrophobic, the tandem repeats can directly mediate adherence to some substrates, such as polystyrene (16). There is significant strain-to-strain variation in the number of tandem repeats, and most strains possess two different-size alleles that specify different numbers of tandem repeats (24,40,71).…”

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Candida albicans Als3, a Multifunctional Adhesin and Invasin

2011

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2Candida albicans is part of the normal human flora, and it grows on mucosal surfaces in healthy individuals. In susceptible hosts, this organism can cause both mucosal and hematogenously disseminated disease. For C. albicans to persist in the host and induce disease, it must be able to adhere to biotic and abiotic surfaces, invade host cells, and obtain iron. The C. albicans hypha-specific surface protein Als3 is a member of the agglutininlike sequence (Als) family of proteins and is important in all of these processes. Functioning as an adhesin, Als3 mediates attachment to epithelial cells, endothelial cells, and extracellular matrix proteins. It also plays an important role in biofilm formation on prosthetic surfaces, both alone and in mixed infection with Streptococcus gordonii. Als3 is one of two known C. albicans invasins. It binds to host cell receptors such as E-cadherin and N-cadherin and thereby induces host cells to endocytose the organism. Als3 also binds to host cell ferritin and enables C. albicans to utilize this protein as a source of iron. Because of its multiple functions and its high expression level in vivo, Als3 is a promising target for vaccines that induce protective cell-mediated and antibody responses. This review will summarize the multiple functions of this interesting and multifunctional protein.Candida spp. are the fourth most common cause of nosocomial bloodstream infections, and Candida albicans accounts for approximately 50% of cases of candidemia (20,67). This organism also causes at least 80% of cases of oropharyngeal and vulvovaginal candidiasis (57, 66). The predominance of C. albicans as a cause of both hematogenously disseminated and mucosal disease suggests that this organism possesses unique virulence factors compared to other species of Candida. One such factor, which is present only in C. albicans, is Als3. This protein plays a key role in multiple processes that are necessary for the organism to colonize the host and cause disease. These processes include adherence to host cells, biofilm formation, host cell invasion, and iron acquisition. Moreover, because Als3 is highly expressed in vivo, it is a promising target for therapeutic antibody and vaccine development. This review will discuss Als3 structure and function, as well as its utility as a therapeutic target. GENETIC AND BIOCHEMICAL CHARACTERISTICS OF Als3The ALS gene family. Als3 is encoded by the ALS3 gene, which is a member of the agglutinin-like sequence (ALS) gene family (23). This family was discovered by Hoyer et al. (24) based on its similarity to Saccharomyces cerevisiae SAG1, which codes for ␣ agglutinin. The ALS gene family has eight members (ALS1 to ALS7 and ALS9) (Fig. 1). These genes encode cell surface proteins that are predicted to share the same overall structure (Fig. 2). At the N terminus is a signal peptide followed by a 300-amino-acid immunoglobulin-like domain and a 104-amino-acid threonine-rich domain that contains ␤-sheets (18,22,47,55). Most Als proteins have adhesin function (18,55,72), an...

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Structure and Function of Glycosylated Tandem Repeats from Candida albicans Als Adhesins

Cited by 57 publications

References 53 publications

Role of cell surface hydrophobicity in Candida albicans biofilm

Role of cell surface hydrophobicity in Candida albicans biofilm

Force-induced formation and propagation of adhesion nanodomains in living fungal cells

Candida albicans Als3, a Multifunctional Adhesin and Invasin

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