Candidly Candida

Hello everyone,
Many will have heard of Candida albicans, the most widespread fungal pathogen among humans and most commonly known as the fungus that causes oral and vaginal thrush. In these normal cases, the fungus is generally non-fatal but C. albicans has a more sinister role in hospitals: it infects patients in hospitals, usually via plastic surfaces that are implanted into the body (like catheters, prosthetic joints, heart implants, etc.). According to the ABC news article, nearly half of the more severe cases result in death - even without fatal consequences, I'm sure we all agree that a fungal infection in your heart is going to be unpleasant! Of course, as is generally the case, the most severe infections can't be treated effectively (of course, being a fungus = eukaryotic cell, C. albicans can't be treated with antibiotics), but some researchers in the UK have characterised a set of glycoproteins (glycoprotein = sugar + protein, for those unaware) that allow C. albicans to infect humans so effectively. They are called Agglutinin-like sequence (Als) glycoproteins and they allow C. albicans to adhere to a wide variety of host cell surface proteins (a major virulence factor of C. albicans. There are multiple Als proteins, and they may be further modified with glycans (i.e. sugars) as well.

The researchers of the paper, Salgado et al. (2011), solved the structures of Als bound with a target protein to investigate the specific mechanism of binding which allows such broad specificity. The main feature of Als proteins is a lysine-59 residue, which is buried in a cleft. The positive side chain of the lysine forms a salt bridge with a carboxylate (COO-) C-terminus of an incoming peptide. This salt bridge stabilises the incoming protein in place and allows the nearby water molecules and protein side chains to form hydrogen bonds with the incoming peptide, 'locking' it in place; the water molecules are important to the broad specificity of Als because they can rearrange to allow more or less space for side chains on the incoming peptide and can form hydrogen bonds in more optimal locations. Thus, the multiple hydrogen bonds keep C. albicans tightly attached to the target cell. This mechanism also provides an idea for a method to inhibit C. albicans infection: by blocking the lysine-59 residue, the whole Als protein binding mechanism is inhibited.

The main toxic effects of C. albicans come from its ability to form 'biofilms'. These are collections of fungal cells that bind together into 'nanoadhesomes' (term from the paper). These biofilms are often implicated in the virulence of bacterial and fungal infections. The biofilm formation is also linked with Als function; another domain of Als facilitates these interactions between different cells.

Als is a busy protein: it has also been suggested that Als can bind to fucose (a sugar) and fucose-related structures (e.g. glycoproteins), further increasing its ability to adhere to cells.

Finally, upregulation of Als (i.e. stimulus to make the cell produce more Als) occurs with upregulation of a nearby (on the chromosome) protease: the authors suggest that this could result in a 'tag-team' effect where the protease 'liberates' the C-terminus of a target protein and the Als binds it, allowing for more binding sites and stronger adhesion.

This is an interesting protein, especially from the author's perspective, because Als doesn't require surface complementarity to bind, just a free C-terminus - this is actually quite unknown in other binding interactions. Also, Als is very flexible, not just in ligand specificity but also physically, giving it the ability to change conformation easily to incorporate more ligands.