Functional and Structural Diversity in the Als Protein Family of Candida albicans
Open accessAbstract
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 substrate-specific 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 beta-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.
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The ALS gene family encodes eight GPI-linked cell surface proteins that mediate binding to diverse host substrates.
“This gene family encodes eight GPI-linked cell surface proteins that mediate binding to diverse host substrates [20][21][22][23][24][25].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
S. cerevisiae expressing Als3 are avidly endocytosed by endothelial cells.
“We found that Saccharomyces cerevisiae expressing Als3 were avidly endocytosed by endothelial cells.”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
S. cerevisiae expressing Als3 bound to both endothelial cells and FaDu oral epithelial cells.
“Also, we found that S. cerevisiae expressing Als3 bound to both endothelial cells and FaDu oral epithelial cells [23].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
Als1 and Als5 can also induce endocytosis, although with considerably less efficiency than Als3.
“Similar experiments suggested that Als1 and Als5 could also induce endocytosis, although with considerably less efficiency than Als3 [23].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
The N-terminal domain of Als proteins contains the substrate-binding region.
“The N-terminal domain contains the substratebinding region [23,26].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
Computer-assisted modeling of the N-termini of Als1, Als3, and Als5 predicts the presence of antiparallel beta sheets that define the immunoglobulin superfamily.
“Computer-assisted modeling of the N-termini of Als1, Als3, and Als5 predicts the presence of antiparallel b sheets that define the immunoglobulin superfamily [23].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
The N-terminal region of Als proteins contains the substrate-binding site.
“Previously, we determined that the N-terminal region of Als proteins contains the substrate-binding site [23,26].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
The Als family of proteins contains six members in addition to Als1 and Als3.
“The Als family of proteins contains six members in addition to Als1 and Als3 [20][21][22][23][24][25].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
When expressed in S. cerevisiae, Als5 induces weak endothelial cell endocytosis similar to that induced by Als1.
“When expressed in S. cerevisiae, Als5 induces weak endothelial cell endocytosis similar to that induced by Als1 [23].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
S. cerevisiae expressing Als1 or Als3 binds to a variety of host constituents, including endothelial cells, epithelial cells, laminin, and fibronectin.
“Previously, we have reported that S. cerevisiae expressing Als1 or Als3 binds to a variety of host constituents, including endothelial cells, epithelial cells, laminin, and fibronectin [23].”
From Als3 Is a Candida albicans Invasin That Binds to Cadherins and Induces Endocytosis by Host Cells (2007) · cites this paper as [23]
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“Als family members are known to interact with several substrates, including host cells and proteins (Hoyer, 2001; Sundstrom, 2002; Sheppard et al., 2004; Kumamoto and Vinces, 2005).”
BackgroundA yeast by any other name: Candida glabrata and its interaction with the host
Kaur, R., Domergue, R., Zupancic, M. L., & Cormack, B. P. (2005) · Current Opinion in Microbiology · doi:10.1016/j.mib.2005.06.012 · Cited by 271 · see citing works
Candida glabrata: A review of its features and resistance
Rodrigues, C. F., Silva, S., & Henriques, M. (2014) · European Journal of Clinical Microbiology & Infectious Diseases · doi:10.1007/s10096-013-2009-3 · Cited by 268 · see citing works
Karkowska‐Kuleta, J., Rąpała‐Kozik, M., & Kozik, A. (2009) · Acta Biochimica Polonica · doi:10.18388/abp.2009_2452 · Cited by 251 · see citing works
“This part contains multiple antiparallel β-sheet domains containing minor αhelical and β-turn components, which indicates that products of ALS genes are members of immunoglobulin family (Sheppard et al., 2004).”
BackgroundComparative genomics of the fungal pathogens Candida dubliniensis and Candida albicansPreprint
Jackson, A. P., Gamble, J. A., Yeomans, T., Moran, G. P., Saunders, D., Harris, D. E., Aslett, M. A., Barrell, J. F., Butler, G., Citiulo, F., et al. (2009) · Genome Research · doi:10.1101/gr.097501.109 · Cited by 212 · see citing works
“…Research 2231 www.genome.org for C. albicans, it does so less efficiently than C. albicans under a wide range of hypha-induction conditions (Stokes et al. 2007) and exhibited low levels of filamentation in infection model experiments (Vilela et al. 2002; Moran et al. 2007; Stokes et al. 2007).”
BackgroundHoefs, S., Mogavero, S., & Hube, B. (2016) · The Journal of Microbiology · doi:10.1007/s12275-016-5514-0 · Cited by 238 · see citing works
“The eight members that are encoded by the ALS gene family (ALS1-7 and ALS9) are cell surface proteins and are glycosylphosphatidylinositol (GPI)linked to the ß-1,6-glucans of the fungal cell wall (Gaur and Klotz, 1997; Hoyer, 2001; Sheppard et al., 2004).”
BackgroundInfluentialSchmidt, C. S., White, C. J., Ibrahim, A. S., Filler, S. G., Fu, Y., Yeaman, M. R., Edwards, J. E., & Hennessey, J. P. (2012) · Vaccine · doi:10.1016/j.vaccine.2012.10.038 · Cited by 233 · see citing works
“It also has both sequence and structural homology with cell surface proteins on Staphylococcus aureus [23].”
BackgroundSelf-citationInteractions of<i>Candida albicans</i>with epithelial cells
Zhu, W., & Filler, S. G. (2010) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01412.x · Cited by 223 · see citing works
“Similar studies suggest that Als1 can also induce epithelial cell endocytosis, although with lower efficiency than Als3 (Sheppard et al., 2004; Phan et al., 2007).”
BackgroundResultInfluentialSelf-citationSilverman, R. J., Nobbs, A. H., Vickerman, M. M., Barbour, M. E., & Jenkinson, H. F. (2010) · Infection and Immunity · doi:10.1128/iai.00685-10 · Cited by 219 · see citing works
“heterologous ALS3 under the alcohol dehydrogenase (ADH) promoter (50).”
BackgroundOrigins of variation in the fungal cell surface
Verstrepen, K., Reynolds, T., & Fink, G. (2004) · Nature Reviews Microbiology · doi:10.1038/nrmicro927 · Cited by 215 · see citing works
Edwards, J. E., Schwartz, M. M., Schmidt, C. S., Sobel, J. D., Nyirjesy, P., Schodel, F., Marchus, E., Lizakowski, M., DeMontigny, E. A., Hoeg, J., et al. (2018) · Clinical Infectious Diseases · doi:10.1093/cid/ciy185 · Cited by 213 · see citing works
Self-citationPark, H., Myers, C. L., Sheppard, D. C., Phan, Q. T., Sanchez, A. A., E. Edwards, J., & Filler, S. G. (2004) · Cellular Microbiology · doi:10.1111/j.1462-5822.2004.00476.x · Cited by 207 · see citing works
“Efg1p is also known to regulate the expression of adhesins, such as Hwp1p, Als1p and Als3p that mediate the binding of C. albicans to oral epithelial cells (Sharkey et al., 1999; Braun and Johnson, 2000; Fu et al., 2002; Sheppard et al., 2004).”
BackgroundSelf-citationVillar, C. C., Kashleva, H., Nobile, C. J., Mitchell, A., & Dongari-Bagtzoglou, A. (2007) · Infection and Immunity · doi:10.1128/iai.00054-07 · Cited by 205 · see citing works
“These mechanisms include expression of host recognition molecules or adhesins 28 (13, 40, 49), ability to exist in reversible morphotypes (5), undergo phenotypic switching 29 (29, 44), and expression of tissue invasion-facilitating enzymes, such as phospholipases 30 and secreted aspartyl proteinases (12, 15, 22, 32, 4…”
BackgroundHoyer, L. L., & Cota, E. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00280 · Cited by 216 · see citing works
“The NT domain was implicated in much of the inferred protein– protein interactions (Loza et al., 2004; Sheppard et al., 2004; Zhao et al., 2006).”
BackgroundMethodInfluentialTorosantucci, A., Chiani, P., Bromuro, C., de Bernardis, F., Palma, A., Liu, Y., Mignogna, G., Maras, B., Colone, M., Stringaro, A., et al. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005392 · Cited by 195 · see citing works
Candida albicans Als3p is required for wild-type biofilm formation on silicone elastomer surfaces.
Zhao, X.-M., Daniels, K., Oh, S.-H., Green, C. B., Yeater, K., Soll, D., & Hoyer, L. (2006) · Microbiology · doi:10.1099/mic.0.28959-0 · Cited by 188 · see citing works
“Another study claimed to demonstrate adhesive specificity within the N-terminal domain of Als5p and Als6p using a domainswapping approach (Sheppard et al., 2004).”
Spellberg, B. J., Ibrahim, A. S., Avanesian, V., Fu, Y., Myers, C., Phan, Q. T., Filler, S. G., Yeaman, M. R., & Edwards, Jr. (2006) · The Journal of Infectious Diseases · doi:10.1086/504691 · Cited by 180 · see citing works
“When compared with one another, Als1p mediates greater adherence to endothelial cells and gelatin but inferior adherence to epithelial cells [6].”
BackgroundInfluentialSelf-citationCandida albicans-epithelial interactions and pathogenicity mechanisms: scratching the surface
Moyes, D., Richardson, J., & Naglik, J. (2015) · Virulence · doi:10.1080/21505594.2015.1012981 · Cited by 171 · see citing works
“cerevisiae over-expression mutants showing increased adherence.(26,31) As well as Hwp1p and Als family proteins, other adhesins have been identified.”
BackgroundWatanabe, N.-A., Miyazaki, M., Horii, T., Sagane, K., Tsukahara, K., & Hata, K. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00731-11 · Cited by 169 · see citing works
“albicans (15, 55), GPI biosynthesis inhibition is expected to lead to the suppression of hyphal growth and reduce adherence of C.”
BackgroundZhao, X.-M., Oh, S.-H., Yeater, K., & Hoyer, L. (2005) · Microbiology · doi:10.1099/mic.0.27763-0 · Cited by 166 · see citing works
“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).”
BackgroundKlis, F. M., Sosinska, G. J., de Groot, P. W. J., & Brul, S. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00541.x · Cited by 165 · see citing works
“…with green fluorescent protein tagging: Pga59 and 62), by immunogold-labeling (Sap 9 and Sap10), or by expression cloning in S. cerevisiae and binding of the transformed cells to antibody- or ligand-coated magnetic beads (the Als protein family, Csa1; Lamarre et al., 2000; Sheppard et al., 2004).”
BackgroundMethodInfluentialKean, R., Rajendran, R., Haggarty, J. H., Townsend, E. R., Short, B., Burgess, K. E., Lang, S., Millington, O. R., Mackay, W. G., Williams, C., et al. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.00258 · Cited by 206 · see citing works
“Als3p shares between 80 and ≥95% homology with collagen binding and clumping factor proteins of S. aureus (Sheppard et al., 2004), therefore the cellular basis for these interactions may be reciprocal.”
BackgroundComprehensive Analysis of Glycosylphosphatidylinositol-Anchored Proteins in <i>Candida albicans</i>
Richard, M. L., & Plaine, A. (2007) · Eukaryotic Cell · doi:10.1128/ec.00297-06 · Cited by 159 · see citing works
“Sheppard and coworkers examined the structural diversity within the Als protein family (49).”
BackgroundYeast Cell Adhesion Molecules Have Functional Amyloid-Forming Sequences
Ramsook, C. B., Tan, C., Garcia, M. C., Fung, R., Soybelman, G., Henry, R., Litewka, A., O'Meally, S., Otoo, H., Khalaf, R. A., et al. (2009) · Eukaryotic Cell · doi:10.1128/ec.00068-09 · Cited by 156 · see citing works
“Cells expressing ScFlo1p were slightly more birefringent than W303-1B (Fig.”
BackgroundInfluentialSpellberg, B., Ibrahim, A., Yeaman, M., Lin, L., Fu, Y., Avanesian, V., Bayer, A., Filler, S., Lipke, P., Otoo, H., et al. (2008) · Infection and Immunity · doi:10.1128/iai.00700-08 · Cited by 156 · see citing works
“aureus clumping factor, and related MSCRAMM proteins (26) influenced us to test the possibility of cross-kingdom protection against C.”
BackgroundMethodInfluentialSelf-citationAspergillus fumigatus MedA governs adherence, host cell interactions and virulence
Gravelat, F., Ejzykowicz, D. E., Chiang, L. Y., Chabot, J., Urb, M., Macdonald, K., al-Bader, N., Filler, S., & Sheppard, D. C. (2009) · Cellular Microbiology · doi:10.1111/j.1462-5822.2009.01408.x · Cited by 144 · see citing works
“Adherence assays The capacity of the various strains of A. fumigatus to adhere to epithelial cells, plastic and endothelial cells was analysed using a modification of our previously described method (Sheppard et al., 2004a).”
MethodSelf-citationGlycan microarray analysis of <i>Candida glabrata</i> adhesin ligand specificity
Zupancic, M. L., Frieman, M., Smith, D., Alvarez, R. A., Cummings, R. D., & Cormack, B. P. (2008) · Molecular Microbiology · doi:10.1111/j.1365-2958.2008.06184.x · Cited by 143 · see citing works
“…of several of the Als proteins have been characterized – for example,Als1,Als3 andAls5 have been found to adhere, to varying degrees, to both epithelial and endothelial cell types, as well as to extracellular matrix proteins (Gaur and Klotz, 1997; Fu et al., 1998; Sheppard et al., 2004).”
BackgroundInfluentialCandida albicans Als Adhesins Have Conserved Amyloid-Forming Sequences
Otoo, H., Lee, K., Qiu, W.-G., & Lipke, P. (2007) · Eukaryotic Cell · doi:10.1128/ec.00309-07 · Cited by 139 · see citing works
“The Ig-like domains mediate adherence, and the TR increase the affinity of the Ig-like region for ligands and can also aggregate yeasts independently of the Ig-like region (12, 20, 24, 25, 29).”
BackgroundWhy does Candida albicans switch?
Soll, D. (2009) · FEMS Yeast Research · doi:10.1111/j.1567-1364.2009.00562.x · Cited by 136 · see citing works
Tati, S., Davidow, P., McCall, A. D., Hwang-Wong, E., Rojas, I. G., Cormack, B. P., & Edgerton, M. (2016) · PLoS Pathogens · doi:10.1371/journal.ppat.1005522 · Cited by 142 · see citing works
“S150-2B pALS1 leu2 his3 trp1 ura3+pALS1 [55] C.”
InfluentialAdherence mechanisms in human pathogenic fungi.
Tronchin, G., Pihet, M., Lopes-Bezerra, L., & Bouchara, J. (2008) · Medical Mycology · doi:10.1080/13693780802206435 · Cited by 129 · see citing works
A Role for Amyloid in Cell Aggregation and Biofilm Formation
Garcia, M. C., Lee, J. T., Ramsook, C. B., Alsteens, D., Dufrêne, Y., & Lipke, P. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017632 · Cited by 128 · see citing works
“Nevertheless, expression in Saccharomyces cerevisiae has shown that Als1p, Als3p and Als5p bind similarly to a variety of substrates and are involved in endothelial cell adhesion, fungal aggregation, and tissue invasion [7,16,17,18,19].”
BackgroundCandida albicans Als proteins mediate aggregation with bacteria and yeasts.
Klotz, S., Gaur, N., Armond, R. L. D., Sheppard, D., Khardori, N., Edwards, J., Lipke, P., & El-azizi, M. (2007) · Medical Mycology · doi:10.1080/13693780701299333 · Cited by 125 · see citing works
Self-citationMurciano, C., Moyes, D., Runglall, M., Tobouti, P., Islam, A., Hoyer, L., & Naglik, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0033362 · Cited by 124 · see citing works
“Previously, a potential role for Als1 and Als5 in epithelial adhesion was suggested [35], which seems inconsistent with our results that demonstrate lack of an adhesive change in C.”
ResultPortrait of Candida Species Biofilm Regulatory Network Genes
Araújo, D., Henriques, M., & Silva, S. M. (2016) · Trends in Microbiology · doi:10.1016/j.tim.2016.09.004 · Cited by 135 · see citing works
Threonine-Rich Repeats Increase Fibronectin Binding in the <i>Candidaalbicans</i> Adhesin Als5p
Rauceo, J. M., De Armond, R., Otoo, H., Kahn, P. C., Klotz, S. A., Gaur, N. K., & Lipke, P. N. (2006) · Eukaryotic Cell · doi:10.1128/ec.00120-06 · Cited by 115 · see citing works
“CD spectroscopy studies have reported that Als5p(1-329) (Ig regions) and Als1p(1-432) (Ig-T regions) fragments have far UV CD spectra with a single minimum close to 212 nm, near the characteristic negative peak for proteins with mostly antiparallel -sheet and very little -helical content (17, 32).”
BackgroundResultInfluentialN-cadherin Mediates Endocytosis of Candida albicans by Endothelial Cells
Phan, Q. T., Fratti, R. A., Prasadarao, N. V., Edwards, J. E., & Filler, S. G. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m412592200 · Cited by 113 · see citing works
Self-citationNobbs, A. H., Vickerman, M. M., & Jenkinson, H. F. (2010) · Eukaryotic Cell · doi:10.1128/ec.00103-10 · Cited by 112 · see citing works
“There is some evidence that Als3p may promote attachment to fibronectin (39).”
BackgroundA study of the Candida albicans cell wall proteome
Castillo, L., Calvo, E., Martinez, A. I., Ruiz-Herrera, J., Valentín, E., López, J., & Sentandreu, R. (2008) · Proteomics · doi:10.1002/pmic.200800110 · Cited by 107 · see citing works
“They are probably involved in epithelial adhesion and invasiveness [14].”
BackgroundStrengthening relationships: amyloids create adhesion nanodomains in yeasts
Lipke, P. N., Garcia, M. C., Alsteens, D., Ramsook, C. B., Klotz, S. A., & Dufrêne, Y. F. (2012) · Trends in Microbiology · doi:10.1016/j.tim.2011.10.002 · Cited by 104 · see citing works
“In the initial unactivated state, Als proteins would bind to each other through rapidly dissociable hydrophobic effect interactions of the TR domains, and probably ligand binding of Ig domains [22, 25, 28, 55].”
BackgroundProteolytic Cleavage of Covalently Linked Cell Wall Proteins by Candida albicans Sap9 and Sap10
Schild, L., Heyken, A., de Groot, P. W. J., Hiller, E., Mock, M., de Koster, C., Horn, U., Rupp, S., & Hube, B. (2011) · Eukaryotic Cell · doi:10.1128/ec.00210-10 · Cited by 104 · see citing works
“Identified proteins belonged to the class of covalently linked GPI-modified cell wall proteins (GPI-CWPs), with functions from cell wall remodeling (Cht2, Ecm33, Pga4 and Rhd3) (14, 37, 39, 56) to host cell interaction and virulence (Ywp1, Als2, Ecm33, and Rhd3) (14, 24, 37, 64) and iron metabolism (Rbt5) (69) (Table…”
BackgroundInfluentialPathophysiological aspects of Aspergillus colonization in disease.
Gago, S., Denning, D., & Bowyer, P. (2018) · Medical Mycology · doi:10.1093/mmy/myy076 · Cited by 104 · see citing works
“86 Recently, the importance of a putative GPI-anchored protein, cspA, in mediating A. fumigatus binding to the host has been evaluated in an in vitro model of infection using A549 alveolar epithelial cells.”
BackgroundCandida-host cell receptor-ligand interactions.
Filler, S. (2006) · Current Opinion in Microbiology · doi:10.1016/j.mib.2006.06.005 · Cited by 104 · see citing works
Self-citationCandida albicans Interactions with Mucosal Surfaces during Health and Disease
Nikou, S.-A., Kichik, N., Brown, R., Ponde, N., Ho, J., Naglik, J., & Richardson, J. (2019) · Pathogens · doi:10.3390/pathogens8020053 · Cited by 103 · see citing works
Biofilm Exopolysaccharides of Pathogenic Fungi: Lessons from Bacteria
Sheppard, D. C., & Howell, P. L. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.r116.720995 · Cited by 125 · see citing works
Self-citationMolecular Mechanism of Aspergillus fumigatus Adherence to Host Constituents
Sheppard, D. (2011) · Current Opinion in Microbiology · doi:10.1016/j.mib.2011.07.006 · Cited by 102 · see citing works
“In this organism, glycosylphosphatidylinositol (GPI) anchored, serine-threonine rich proteins containing internal tandem repeats have been described as key effectors of fungal adherence [14,15].”
Self-citationAdvancements and challenges in antifungal therapeutic development
Puumala, E., Fallah, S., Robbins, N., & Cowen, L. E. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00142-23 · Cited by 118 · see citing works
“…an immunodominant C. albicans cell wall protein that is characterized by three domains: an N-terminal region, which is conserved among Als proteins; a central portion containing variable tandem repeats; and a serine-rich C-terminal region containing a glycosylphosphatidylinositol anchor (131, 132).”
BackgroundGenetic and epigenetic mechanisms underlying cell-surface variability in protozoa and fungi.
Verstrepen, K., & Fink, G. (2009) · Annual Review of Genetics · doi:10.1146/annurev-genet-102108-134156 · Cited by 97 · see citing works
Sztukowska, M. N., Dutton, L. C., Delaney, C., Ramsdale, M., Ramage, G., Jenkinson, H. F., Nobbs, A. H., & Lamont, R. J. (2018) · mBio · doi:10.1128/mbio.00202-18 · Cited by 96 · see citing works
NDV-3 protects mice from vulvovaginal candidiasis through T- and B-cell immune response
Ibrahim, A. S., Luo, G., Gebremariam, T., Lee, H.-K., Schmidt, C. S., Hennessey, J. P., French, S. W., Yeaman, M. R., Filler, S. G., & Edwards, J. E. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.09.016 · Cited by 97 · see citing works
“albicans cell surface agglutinin-like sequence 3 protein (Als3p), plays a key role in multiple processes that are necessary for disease initiation and progression including adherence to host cells [10, 11], biofilm formation [11, 12], host cell invasion [13], and iron acquisition [14].”
BackgroundSelf-citationCandida albicans CUG Mistranslation Is a Mechanism To Create Cell Surface Variation
Miranda, I., Silva-Dias, A., Rocha, R., Teixeira-Santos, R., Coelho, C., Gonçalves, T., Santos, M. A. S., Pina-Vaz, C., Solis, N., Filler, S., et al. (2013) · mBio · doi:10.1128/mbio.00285-13 · Cited by 96 · see citing works
“albicans ALS3-Leu and ALS3-Ser genes (20).”
BackgroundMethodInfluentialSelf-citationLi, F., & Palecek, S. (2008) · Microbiology · doi:10.1099/mic.0.2007/013789-0 · Cited by 95 · see citing works
“Adherence activity of the GPI-anchored proteins has commonly been ascribed to the N-terminal domains of these proteins because deletions in these regions usually abrogate binding activity (Frieman et al., 2002; Loza et al., 2004; Sheppard et al., 2004; Staab & Sundstrom, 1998; Wojciechowicz et al., 1993).”
BackgroundGenomewide Expression Profile Analysis of the Candida glabrata Pdr1 Regulon
Caudle, K. E., Barker, K. S., Wiederhold, N. P., Xu, L., Homayouni, R., & Rogers, P. D. (2010) · Eukaryotic Cell · doi:10.1128/ec.00073-10 · Cited by 92 · see citing works
“albicans have been shown to confer distinct adhesion profiles toward human proteins and cells (29).”
BackgroundMechanisms of Candida albicans Trafficking to the Brain
Liu, Y., Mittal, R., Solis, N. V., Prasadarao, N. V., & Filler, S. G. (2011) · PLoS Pathogens · doi:10.1371/journal.ppat.1002305 · Cited by 93 · see citing works
“albicans to HUVECs and HBMECs grown in 6-well tissue culture plates was measured by a modification of our previously described method [25].”
BackgroundMethodInfluentialSelf-citationAdhesins of Yeasts: Protein Structure and Interactions
Willaert, R. (2018) · Journal of Fungi · doi:10.3390/jof4040119 · Cited by 92 · see citing works
Salgado, P., Yan, R., Taylor, J. D., Burchell, L., Jones, R., Hoyer, L., Matthews, S., Simpson, P., & Cota, E. (2011) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1103496108 · Cited by 91 · see citing works
“Despite the ability to recognize a range of unrelated substrates, there are documented differences in ligand specificity between Als proteins (10, 11), potentially due to variations in C-terminal peptide sequences that can be accommodated in the binding clefts of their respective N-terminal adhesins.”
BackgroundThe multitude of targets for the immune system and drug therapy in the fungal cell wall.
Nimrichter, L., Rodrigues, M., Rodrigues, E., & Travassos, L. (2005) · Microbes and infection · doi:10.1016/j.micinf.2005.03.002 · Cited by 91 · see citing works
Protein Glycosylation in Candida
Mora-Montes, H. M., Ponce‐Noyola, P., Villagómez-Castro, J. C., Gow, N. A. R., Flores-Carreón, A., & López-Romero, E. (2009) · Future Microbiology · doi:10.2217/fmb.09.88 · Cited by 90 · see citing works
Aspergillus fumigatus CalA Binds to Integrin α5β1 and Mediates Host Cell Invasion
Liu, H., Lee, M. J., Solis, N., Phan, Q., Swidergall, M., Ralph, B., Ibrahim, A., Sheppard, D., & Filler, S. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.211 · Cited by 88 · see citing works
Self-citationGrubb, S. E. W., Murdoch, C., Sudbery, P. E., Saville, S. P., Lopez-Ribot, J. L., & Thornhill, M. H. (2008) · Infection and Immunity · doi:10.1128/iai.00332-08 · Cited by 87 · see citing works
“These include proteins with integrin-like properties (reviewed in references 32 and 36), Candida agglutinin-like sequence (ALS) gene products (72, 84), and mannans (57).”
BackgroundLinder, T., & Gustafsson, C. M. (2007) · Fungal Genetics and Biology · doi:10.1016/j.fgb.2007.08.002 · Cited by 80 · see citing works
Modular determinants of antimicrobial activity in platelet factor-4 family kinocidins.
Yeaman, M., Yount, N., Waring, A., Gank, K. D., Kupferwasser, D., Wiese, R., Bayer, A., & Welch, W. (2007) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamem.2006.11.010 · Cited by 86 · see citing works
“Secondary structures of cPMP library peptides were assessed by circular dichroism (CD) as previously detailed [22].”
MethodSelf-citationRomo, J. A., & Kumamoto, C. A. (2020) · Journal of Fungi · doi:10.3390/jof6010016 · Cited by 97 · see citing works
Ibrahim, A. S., Spellberg, B. J., Avenissian, V., Fu, Y., Filler, S. G., & Edwards, J. E. (2005) · Infection and Immunity · doi:10.1128/iai.73.2.999-1005.2005 · Cited by 83 · see citing works
“albicans adherence to endothelial cells (32), and because of its potential immunological cross-reactivity with other members of the Als family of proteins (54).”
BackgroundSelf-citationIbrahim, A., Spellberg, B., Avanesian, V., Fu, Y., & Edwards, J. (2006) · Infection and Immunity · doi:10.1128/iai.74.5.3039-3041.2006 · Cited by 83 · see citing works
“A high degree of purity (90%) was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis as well as circular dichroism and Fourier transform infrared microscopy, as described previously ( 10 ).”
BackgroundSelf-citationFungal Cell Wall Proteins and Signaling Pathways Form a Cytoprotective Network to Combat Stresses
Ibe, C., & Munro, C. A. (2021) · Journal of Fungi · doi:10.3390/jof7090739 · Cited by 86 · see citing works
What We Do Not Know about Fungal Cell Adhesion Molecules
Lipke, P. (2018) · Journal of Fungi · doi:10.3390/jof4020059 · Cited by 81 · see citing works
Lin, J., Oh, S.-H., Jones, R., Garnett, J., Salgado, P., Rusnakova, S., Matthews, S., Hoyer, L., & Cota, E. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.547877 · Cited by 81 · see citing works
“Initial speculation about the Als ligand-binding mechanism suggested that it occurs by interactions between the NT-Als surface and the surface of the ligand (8, 16, 32).”
BackgroundMartínez-López, R., Park, H., Myers, C., Gil, C., & Filler, S. (2006) · Eukaryotic Cell · doi:10.1128/ec.5.1.140-147.2006 · Cited by 81 · see citing works
“albicans hyphae, where it functions as an adhesin (10, 11, 27).”
BackgroundSelf-citationFungal invasion of epithelial cells
Yang, W., Yan, L., Wu, C., Zhao, X., & Tang, J. (2014) · Microbiological Research · doi:10.1016/j.micres.2014.02.013 · Cited by 79 · see citing works
“2004; Sheppard et al. 2004; Rauceo et al. 2006), the Nerminal domain is composed of a signal peptide followed by an mmunoglobulin-like domain and a threonine-rich domain conaining anti-parallel -sheets (Hoyer and Hecht 2001; Sheppard t al.”
BackgroundInfluentialInnate immune cell response upon Candida albicans infection
Qin, Y.-L., Zhang, L., Xu, Z., Zhang, J.-Y., Jiang, Y.-Y., Cao, Y.-B., & Yan, T.-H. (2016) · Virulence · doi:10.1080/21505594.2016.1138201 · Cited by 79 · see citing works
Alves, C., Wei, X.-Q., Silva, S., Azeredo, J., Henriques, M., & Williams, D. (2014) · Journal of Infection · doi:10.1016/j.jinf.2014.06.002 · Cited by 79 · see citing works
Gene Overexpression/Suppression Analysis of Candidate Virulence Factors of Candida albicans
Fu, Y., Luo, G., Spellberg, B., Edwards, J., & Ibrahim, A. (2008) · Eukaryotic Cell · doi:10.1128/ec.00445-07 · Cited by 72 · see citing works
“albicans include proteins that mediate adherence to and invasion of host tissues (43), morphological change from yeast to hyphae (29, 30), secretion of lytic enzymes (17, 27, 41), maintenance of cell wall integrity (55), and avoidance of the host immune response (39).”
BackgroundSelf-citationStructural congruence among membrane-active host defense polypeptides of diverse phylogeny.
Yount, N., & Yeaman, M. (2006) · Biochimica et Biophysica Acta · doi:10.1016/j.bbamem.2006.03.027 · Cited by 72 · see citing works
Self-citationFernández-Álvarez, A., Elías-Villalobos, A., & Ibeas, J. (2009) · The Plant Cell Online · doi:10.1105/tpc.109.065839 · Cited by 71 · see citing works
“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).”
BackgroundRas Signaling Gets Fine-Tuned: Regulation of Multiple Pathogenic Traits of Candida albicans
Inglis, D. O., & Sherlock, G. (2013) · Eukaryotic Cell · doi:10.1128/ec.00094-13 · Cited by 65 · see citing works
“This family, and Als3 in particular, is involved in cell adhesion and mediates attachment to endothelial cells (63), epithelial cells, and extracellular matrix proteins (64).”
BackgroundHan, G., Liu, N., Li, C., Tu, J., Li, Z., & Sheng, C. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00102 · Cited by 85 · see citing works
Green, C. B., Zhao, X.-M., Yeater, K., & Hoyer, L. (2005) · Microbiology · doi:10.1099/mic.0.27696-0 · Cited by 68 · see citing works
“One example is the ALS (agglutinin-like sequence) gene family that encodes cell-surface glycoproteins involved in adhesion to host surfaces and potentially other cellular processes (Gaur & Klotz, 1997; Hoyer, 2001; Fu et al., 2002; Zhao et al., 2004; Sheppard et al., 2004).”
Background
- Authors
- Sheppard, D. C., Yeaman, M. R., Welch, W. H., Phan, Q. T., Fu, Y., Ibrahim, A. S., Filler, S. G., Zhang, M., Waring, A. J., & Edwards, J. E.
- Affiliations
- University of California, Los Angeles (US)
- University of Nevada, Reno (US)
- California State University, Long Beach (US)
- Corresponding author
- Sheppard, Donald C.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-07
- Volume
- 279
- Issue
- 29
- Pages
- 30480-30489
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1968095975
- Cited by
- 300
- References
- 59
- Citations by year
- 2026: 9 · 2025: 7 · 2024: 5 · 2023: 9 · 2022: 10 · 2021: 15 · 2020: 15 · 2019: 7 · 2018: 14 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 27 · 2013: 16 · 2012: 13
- FWCI
- 6.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (P01 AI-37194, R01AI019990, R01 AI-48031, R03AI054531, R01-AI19990, R01AI054928, R01AI048031, P01AI037194)
- National Institute of Dental and Craniofacial Research (R01DE013974, 5R01 DE13974)
- National Center for Research Resources (M01RR000425, M01-RR00425)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- Candida albicans, fungal adhesion, endothelial cell invasion, N-terminal domain, antiparallel beta-sheet, cell wall proteins, host-pathogen interaction, fusion protein
- MeSH terms
- Amino Acid Sequence, Candida albicans, Cell Adhesion, Cell Wall, Circular Dichroism, Cloning, Molecular, Endothelium, Vascular, Epithelial Cells, Flow Cytometry, Fungal Proteins, Multigene Family, Humans, Membrane Glycoproteins, Models, Molecular, Molecular Sequence Data, Plasmids, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Substrate Specificity, Cell Adhesion Molecules, Polymerase Chain Reaction, Protein Structure, Secondary, Protein Structure, Tertiary, Spectroscopy, Fourier Transform Infrared, DNA Primers, Amino Acid Motifs, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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