| Structural highlights
Function
ALS3_CANAL Cell surface adhesion protein which mediates both yeast-to-host tissue adherence and yeast aggregation. Plays an important role in the biofilm formation and pathogenesis of C.albicans infections. Necessary for C.albicans to bind to N-cadherin on endothelial cells and E-cadherin on oral epithelial cells and subsequent endocytosis by these cells. During disseminated infection, mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
The adhesive phenotype of Candida albicans contributes to its ability to colonize the host and cause disease. Als proteins are one of the most widely studied C. albicans virulence attributes; deletion of ALS3 produces the greatest reduction in adhesive function. Although adhesive activity is thought to reside within the N-terminal domain of Als proteins (NT-Als), the molecular mechanism of adhesion remains unclear. We designed mutations in NT-Als3 that test the contribution of the peptide-binding cavity (PBC) to C. albicans adhesion, and assess the adhesive properties of other NT-Als3 features in the absence of a functional PBC. Structural analysis of purified loss-of-PBC-function mutant proteins showed that the mutations did not alter the overall structure or surface properties of NT-Als3. The mutations were incorporated into full-length ALS3 and integrated into the ALS3 locus of a deletion mutant, under control of the native ALS3 promoter. PBC-mutant phenotype was evaluated in assays using monolayers of human pharyngeal epithelial (FaDu) and umbilical vein endothelial (HUVEC) cells, and freshly collected human buccal epithelial cells (BEC) in suspension. Loss of PBC function resulted in an adhesion phenotype that was indistinguishable from the deltaals3/deltaals3 strain. The adhesive contribution of the Als3 amyloid-forming-region (AFR) was also tested using these methods. C. albicans strains producing cell-surface Als3 in which the amyloidogenic potential was destroyed, showed little contribution of the AFR to adhesion, instead suggesting an aggregative function for the AFR. Collectively, these results demonstrate the essential and principal role of the PBC in Als3 adhesion.
The Peptide-Binding Cavity is Essential for Als3-mediated Adhesion of Candida albicans to Human Cells.,Lin J, Oh SH, Jones R, Garnett JA, Salgado PS, Rusnakova S, Matthews S, Hoyer LL, Cota E J Biol Chem. 2014 May 6. pii: jbc.M114.547877. PMID:24802757[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sheppard DC, Yeaman MR, Welch WH, Phan QT, Fu Y, Ibrahim AS, Filler SG, Zhang M, Waring AJ, Edwards JE Jr. Functional and structural diversity in the Als protein family of Candida albicans. J Biol Chem. 2004 Jul 16;279(29):30480-9. doi: 10.1074/jbc.M401929200. Epub 2004 , May 5. PMID:15128742 doi:http://dx.doi.org/10.1074/jbc.M401929200
- ↑ Zhao X, Oh SH, Cheng G, Green CB, Nuessen JA, Yeater K, Leng RP, Brown AJ, Hoyer LL. ALS3 and ALS8 represent a single locus that encodes a Candida albicans adhesin; functional comparisons between Als3p and Als1p. Microbiology. 2004 Jul;150(Pt 7):2415-28. PMID:15256583 doi:http://dx.doi.org/10.1099/mic.0.26943-0
- ↑ Nobile CJ, Andes DR, Nett JE, Smith FJ, Yue F, Phan QT, Edwards JE, Filler SG, Mitchell AP. Critical role of Bcr1-dependent adhesins in C. albicans biofilm formation in vitro and in vivo. PLoS Pathog. 2006 Jul;2(7):e63. doi: 10.1371/journal.ppat.0020063. PMID:16839200 doi:http://dx.doi.org/10.1371/journal.ppat.0020063
- ↑ Klotz SA, Gaur NK, De Armond R, Sheppard D, Khardori N, Edwards JE Jr, Lipke PN, El-Azizi M. Candida albicans Als proteins mediate aggregation with bacteria and yeasts. Med Mycol. 2007 Jun;45(4):363-70. doi: 10.1080/13693780701299333. PMID:17510860 doi:http://dx.doi.org/10.1080/13693780701299333
- ↑ Nobile CJ, Schneider HA, Nett JE, Sheppard DC, Filler SG, Andes DR, Mitchell AP. Complementary adhesin function in C. albicans biofilm formation. Curr Biol. 2008 Jul 22;18(14):1017-24. doi: 10.1016/j.cub.2008.06.034. PMID:18635358 doi:http://dx.doi.org/10.1016/j.cub.2008.06.034
- ↑ Aoki W, Kitahara N, Miura N, Morisaka H, Kuroda K, Ueda M. Profiling of adhesive properties of the agglutinin-like sequence (ALS) protein family, a virulent attribute of Candida albicans. FEMS Immunol Med Microbiol. 2012 Jun;65(1):121-4. doi:, 10.1111/j.1574-695X.2012.00941.x. Epub 2012 Mar 6. PMID:22321066 doi:http://dx.doi.org/10.1111/j.1574-695X.2012.00941.x
- ↑ Monroy-Perez E, Sainz-Espunes T, Paniagua-Contreras G, Negrete-Abascal E, Rodriguez-Moctezuma JR, Vaca S. Frequency and expression of ALS and HWP1 genotypes in Candida albicans strains isolated from Mexican patients suffering from vaginal candidosis. Mycoses. 2012 May;55(3):e151-7. doi: 10.1111/j.1439-0507.2012.02188.x. Epub 2012 , Mar 19. PMID:22429754 doi:http://dx.doi.org/10.1111/j.1439-0507.2012.02188.x
- ↑ Fanning S, Xu W, Solis N, Woolford CA, Filler SG, Mitchell AP. Divergent targets of Candida albicans biofilm regulator Bcr1 in vitro and in vivo. Eukaryot Cell. 2012 Jul;11(7):896-904. doi: 10.1128/EC.00103-12. Epub 2012 Apr, 27. PMID:22544909 doi:http://dx.doi.org/10.1128/EC.00103-12
- ↑ Fu Y, Phan QT, Luo G, Solis NV, Liu Y, Cormack BP, Edwards JE Jr, Ibrahim AS, Filler SG. Investigation of the function of Candida albicans Als3 by heterologous expression in Candida glabrata. Infect Immun. 2013 Jul;81(7):2528-35. doi: 10.1128/IAI.00013-13. Epub 2013 Apr, 29. PMID:23630968 doi:http://dx.doi.org/10.1128/IAI.00013-13
- ↑ Alsteens D, Van Dijck P, Lipke PN, Dufrene YF. Quantifying the forces driving cell-cell adhesion in a fungal pathogen. Langmuir. 2013 Nov 5;29(44):13473-80. doi: 10.1021/la403237f. Epub 2013 Oct 23. PMID:24152214 doi:http://dx.doi.org/10.1021/la403237f
- ↑ Dutton LC, Nobbs AH, Jepson K, Jepson MA, Vickerman MM, Aqeel Alawfi S, Munro CA, Lamont RJ, Jenkinson HF. O-mannosylation in Candida albicans enables development of interkingdom biofilm communities. mBio. 2014 Apr 15;5(2):e00911. doi: 10.1128/mBio.00911-14. PMID:24736223 doi:http://dx.doi.org/10.1128/mBio.00911-14
- ↑ Lin J, Oh SH, Jones R, Garnett JA, Salgado PS, Rusnakova S, Matthews S, Hoyer LL, Cota E. The Peptide-Binding Cavity is Essential for Als3-mediated Adhesion of Candida albicans to Human Cells. J Biol Chem. 2014 May 6. pii: jbc.M114.547877. PMID:24802757 doi:http://dx.doi.org/10.1074/jbc.M114.547877
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