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Originally published In Press as doi:10.1074/jbc.M401929200 on May 5, 2004

J. Biol. Chem., Vol. 279, Issue 29, 30480-30489, July 16, 2004
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Functional and Structural Diversity in the Als Protein Family of Candida albicans*

Donald C. Sheppard, Supported by a Clinician Scientist training grant from the Canadian Institutes of Health Research,ab Michael R. Yeaman,acd William H. Welch,de Quynh T. Phan,a Yue Fu,ac Ashraf S. Ibrahim,acf Scott G. Filler,acg Mason Zhang,h Alan J. Waring,ac and John E. Edwards, Jr.ai

From the aSt. Johns Cardiovascular Research Center, Division of Infectious Diseases, Department of Medicine, Harbor-UCLA Research and Education Institute, Torrance, California 90502, the cDavid Geffen School of Medicine at UCLA, Los Angeles, California 90024, the eDepartment of Biochemistry, University of Nevada, Reno, Nevada 89507, and the hDepartment of Biological Sciences, California State University, Long Beach, California 90840

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.

Received for publication, February 22, 2004 , and in revised form, April 30, 2004.

* This research was supported by National Institutes of Health (NIH) Grants PO1 AI37194 and RO1 AI19990 (to J. E. E.) and MO1 RR00425. Selcon CD analysis used the DICHROWEB site on the World Wide Web and is supported by grants to the BBSRC Centre for Protein and Membrane Structure and Dynamics, Daresbury Laboratory, Birkbeck College, University of London. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

d Supported by NIH Grant RO1AI-48031.

f Supported by NIH Grant RO3 AI054531 and a Burroughs Wellcome New Investigator Award in molecular pathogenic mycology.

g Supported by NIH Grants 5RO1 DE13974 and 1RO1 AI054928.

i Recipient of a Bristol Myers Squibb Unrestricted Research Award.

b To whom correspondence should be addressed. Tel.: 310-222-3813; Fax: 310-782-2016; E-mail: dsheppard{at}rei.edu.


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