Functional and Structural Diversity in the Als Protein Family of Candida albicans

Abstract

The human fungal pathogen Candida albicans colonizes and invades a wide range of host tissues. Adherence to host constituents plays an important role in this process. Two members of the C. albicans Als protein family (Als1p and Als5p) have been found to mediate adherence; however, the functions of other members of this family are unknown. In this study, members of the ALS gene family were cloned and expressed in Saccharomyces cerevisiae to characterize their individual functions. Distinct Als proteins conferred distinct adherence profiles to diverse host substrates. Using chimeric Als5p-Als6p constructs, the regions mediating substratespecific adherence were localized to the N-terminal domains in Als proteins. Interestingly, a subset of Als proteins also mediated endothelial cell invasion, a previously unknown function of this family. Consistent with these results, homology modeling revealed that Als members contain anti-parallel ␤-sheet motifs interposed by extended regions, homologous to adhesins or invasins of the immunoglobulin superfamily. This finding was confirmed using circular dichroism and Fourier transform infrared spectrometric analysis of the N-terminal domain of Als1p. Specific regions of amino acid hypervariability were found among the N-terminal domains of Als proteins, and energy-based models predicted similarities and differences in the N-terminal domains that probably govern the diverse function of Als family members. Collectively, these results indicate that the structural and functional diversity within the Als family provides C. albicans with an array of cell wall proteins capable of recognizing and interacting with a wide range of host constituents during infection.

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…bacteremia (43)(44)(45)(46)(47)(48). The adoptive transfer of CD4 + T cells but not B220 + B cells from immunized mice afforded protection (47,48).…”

“…Its immunogen is engineered from the agglutinin-like sequence 3 (Als3) adhesin/invasin of Candida albicans, which we discovered to be a structural homolog of S. aureus adhesins (43). NDV-3 is believed to cross-protect against S. aureus and C. albicans due to sequence (T-cell) and conformational (B-cell) epitopes paralleled in both organisms (44).…”

Analysis of the Candida albicans Als2p and Als4p adhesins suggests the potential for compensatory function within the Als family

“…Adhesive function has been shown for Als1p and Als3p in C. albicans (Fu et al, 2002;Zhao et al, 2004). Overproduction of other Als proteins in Saccharomyces cerevisiae produced an adherent phenotype for this normally non-adherent organism, suggesting they may also play a role in C. albicans adhesion (Gaur & Klotz, 1997;Sheppard et al, 2004).…”

TheO-Mannosyltransferase PMT4 Is Essential for Normal Appressorium Formation and Penetration inUstilago maydis

“…Fungal adhesion to hard, hydrophobic surfaces and the presence of various chemical signals are required for effective appressorium formation and plant penetration (Howard et al, 1991;Lee and Dean, 1993;Gilbert et al, 1996). Cell wall glycoproteins have been identified as fungal adhesives and have been implicated in host cell adhesion in many organisms (Gaur and Klotz, 1997;Buck and Andrews, 1999;Frieman et al, 2002;Sheppard et al, 2004). These studies show that blocking access to glycoproteins with sugar group binding compounds, such as concanavalin A, interferes with the adhesive capacity of fungal cells (Buck and Andrews, 1999).…”