Functional and structural diversity in the Als protein family of Candida albicans.
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.
Sheppard
Donald C
DC
St. Johns Cardiovascular Research Center, Division of Infectious Diseases, Department of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California 90502, USA. dsheppard@rei.edu
Yeaman
Michael R
MR
Welch
William H
WH
Phan
Quynh T
QT
Fu
Yue
Y
Ibrahim
Ashraf S
AS
Filler
Scott G
SG
Zhang
Mason
M
Waring
Alan J
AJ
Edwards
John E
JE
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002176:Candida albicans / Q000378:metabolism*; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D002473:Cell Wall / Q000378:metabolism; D002942:Circular Dichroism; D003001:Cloning, Molecular; D017931:DNA Primers / Q000737:chemistry; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005434:Flow Cytometry; D005656:Fungal Proteins / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D017550:Spectroscopy, Fourier Transform Infrared; D013379:Substrate Specificity
C109455:ALA1 protein, Candida albicans; C093538:ALS1 protein, Candida albicans; C413710:ALS6 protein, Candida albicans; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D005656:Fungal Proteins; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins