Towards understanding the novel adhesin function of Candida albicans phosphoglycerate mutase at the pathogen cell surface: some structural analysis of the interactions with human host extracellular matrix proteins

Abstract

Although many atypical proteinaceous cell wall components that belong to a group of multitasking, "moonlighting" proteins, have been repeatedly identified in numerous pathogenic microorganisms, their novel extracellular functions and secretion mechanisms remain largely unrecognized. In Candida albicans, one of the most common fungal pathogens in humans, phosphoglycerate mutase (Gpm1) - a cytoplasmic enzyme involved in the glycolysis pathway - has been shown to occur on the cell surface and has been identified as a potentially important virulence factor. In this study, we demonstrated tight binding of C. albicans Gpm1 to the candidal cell surface, thus suggesting that the readsorption of soluble Gpm1 from the external environment could be a likely mechanism leading to the presence of this moonlighting protein on the pathogen surface. Several putative Gpm1-binding receptors on the yeast surface were identified. The affinities of Gpm1 to human vitronectin (VTR) and fibronectin (FN) were characterized with surface plasmon resonance measurements, and the dissociation constants of the complexes formed were determined to be in the order of 10–8 M. The internal Gpm1 sequence motifs, directly interacting with VTR (aa 116-158) and FN (aa 138-175) were mapped using chemical crosslinking and mass spectrometry. Synthetic peptides with matching sequences significantly inhibited formation of the Gpm1-VTR and Gpm1-FN complexes. A molecular model of the Gpm1-VTR complex was developed. These results provide the first structural insights into the adhesin function of candidal surface-exposed Gpm1.

A novel mannose‐containing sialoprotein adhesin involved in the binding of Candida albicans cells to DMBT1

“…Recently, Satala et al. (2021) identified ribosomal protein L10a in the cell wall proteins of C. albicans by LC‐MS/MS analysis, and their results support our findings. Further studies are necessary to identify it and clarify the function of surface‐localized L10a using a recombinant version of it.…”

“…Several ribosomal proteins were demonstrated to be localized on the surface of pathogens (Singh et al, 2002;Spence & Clark, 2000). Recently, Satala et al (2021) In conclusion, we demonstrated that C. albicans binds to DMBT1…”

Living together: The role of Candida albicans in the formation of polymicrobial biofilms in the oral cavity

“…Much less characterized are fungal surface‐exposed proteins classified into a group of multitasking “moonlighting” proteins (Chaffin et al, 1998). They are represented by originally cytosolic proteins, involved in basic metabolic processes within the cell (Satala, Satala, et al, 2021; Satala, Zelazna, et al, 2021), such as enolase, but also in cell wall remodeling during cell division and yeast‐to‐mycelium transition (Reyna‐Beltrán et al, 2018). However, after secretion into the extracellular environment and further readsorption on the fungal cell surface, they serve as novel adhesion platforms and strongly interact with human cells and selected proteins (Karkowska‐Kuleta et al, 2021; Satala et al, 2020), although their secretion pathways remain enigmatic since they do not possess any signaling sequences (Karkowska‐Kuleta & Kozik, 2014).…”

Similarities and Differences among Species Closely Related to Candida albicans: C. tropicalis, C. dubliniensis, and C. auris

“…Candida species belonging to the CTG clade have evolved multiple virulence factors that are used at different stages of infection in interactions with host proteins and cells and in the evasion of the immune system. Although the set of virulence factors differs within the CTG clade and their expression depends on the type of strain and the stage of infection [31], they involve primarily the production of different classes of proteins, including adhesins and a wide spectrum of hydrolytic enzymes (Figure 2) [32][33][34][35]. Comparative genomic analyses indicated that for C. albicans, a significant enrichment compared to nonpathogenic yeasts was found for genes encoding secreted proteases and lipases, acid sphingomyelinases, cytochromes P450, and various transporters.…”

“…In addition to classic adhesive proteins, this function is also performed by some cytosolic proteins, called moonlighting proteins, and located on the surface of yeast cells, where they perform completely different functions than at the primary location [44,45]. For example, C. albicans cell wall-associated glyceraldehyde-3-phosphate dehydrogenase (Tdh3), an enzyme originally involved in the glycolysis pathway, has a high affinity for extracellular matrix (ECM) components such as fibronectin and laminin [46] or other glycolytic enzymes, phosphoglycerate mutase 1 (Gpm1) which allows adhesion to umbilical vein endothelial cells (HUVEC) and keratinocytes (HaCaT) [47] and to vitronectin and fibronectin [35] and triosephosphate isomerase (Tpi1), which interact with several ECM proteins [48]. C. albicans enolase (Eno1) was also indicated as an abundant moonlighting protein responsible for binding of human high-molecular-weight kininogen (HK), prekallikrein, coagulation factor XII, and plasminogen [34,49,50].…”