| Structural highlights
Function
PRA1_CANAL Cell surface protein involved in the host-parasite interaction during candidal infection (PubMed:17277107, PubMed:19850343, PubMed:20504767, PubMed:20644161, PubMed:21212281, PubMed:21245270, PubMed:21820180, PubMed:22074954, PubMed:22761575, PubMed:22844116, PubMed:9440517). With MP65, represents a major component of the biofilm matrix (PubMed:17277107). As a surface protein, binds the two human complement regulators CFH and CFHR1, as well as plasminogen PLG, mediates complement evasion and extra-cellular matrix interaction and/or degradation (PubMed:19850343, PubMed:20504767). As a released protein, enhances complement control in direct vicinity of the yeast and thus generates an additional protective layer which controls host complement attack, assisting the fungus in escaping host surveillance (PubMed:17277107, PubMed:19850343). Binds to host fluid-phase C3 and blocks cleavage of C3 to C3a and C3b, leading to inhibition of complement activation and protection from uptake of C.albicans by human macrophages (PubMed:20644161). Also mediates human complement control and complement evasion through binding to C4BPA, another human complement inhibitor, as well as through binding to host integrin alpha-M/beta-2 (PubMed:21212281, PubMed:21245270, PubMed:21820180, PubMed:22844116). Binds zinc from its environment and then reassociates with ZRT1 to acquire this essential metal (PubMed:22761575).[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]
Publication Abstract from PubMed
Candida albicans causes over 400,000 life-threatening, and an additional half a billion of mucosal infections annually. In response to infection, the host limits essential micronutrient availability, including zinc, to restrict growth of the invading pathogen. As assimilation of zinc is essential for C. albicans pathogenicity, limitation induces secretion of the zincophore protein Pra1 to scavenge zinc from the host. Pra1 also plays a number of important roles in host-pathogen interactions and is conserved in most fungi. However, the structure of fungal zincophores is unknown. Here, we present cryo-EM structures of C. albicans Pra1 in apo- and zinc-bound states, at 2.8 and 2.5 A resolution respectively. Our work reveals a hexameric ring with multiple zinc binding sites. Through genetic studies, we show that these sites are essential for C. albicans growth under zinc restriction but do not affect the inflammatory properties of Pra1. These data create a foundation for future work to explore the structural basis of Pra1-mediated host-pathogen interactions, C. albicans zinc uptake, as well as therapeutics development.
Structural insights into mechanisms of zinc scavenging by the Candida albicans zincophore Pra1.,Nore A, Roselletti E, Chakraborty T, Sarkka N, Perera RL, Wilson D, Syrjanen JL Nat Commun. 2025 Nov 28;16(1):10753. doi: 10.1038/s41467-025-65782-0. PMID:41315346[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Soloviev DA, Fonzi WA, Sentandreu R, Pluskota E, Forsyth CB, Yadav S, Plow EF. Identification of pH-regulated antigen 1 released from Candida albicans as the major ligand for leukocyte integrin alphaMbeta2. J Immunol. 2007 Feb 15;178(4):2038-46. PMID:17277107 doi:10.4049/jimmunol.178.4.2038
- ↑ Luo S, Poltermann S, Kunert A, Rupp S, Zipfel PF. Immune evasion of the human pathogenic yeast Candida albicans: Pra1 is a Factor H, FHL-1 and plasminogen binding surface protein. Mol Immunol. 2009 Dec;47(2-3):541-50. PMID:19850343 doi:10.1016/j.molimm.2009.07.017
- ↑ Agarwal V, Asmat TM, Luo S, Jensch I, Zipfel PF, Hammerschmidt S. Complement regulator Factor H mediates a two-step uptake of Streptococcus pneumoniae by human cells. J Biol Chem. 2010 Jul 23;285(30):23486-95. PMID:20504767 doi:10.1074/jbc.M110.142703
- ↑ Luo S, Hartmann A, Dahse HM, Skerka C, Zipfel PF. Secreted pH-regulated antigen 1 of Candida albicans blocks activation and conversion of complement C3. J Immunol. 2010 Aug 15;185(4):2164-73. PMID:20644161 doi:10.4049/jimmunol.1001011
- ↑ Luo S, Blom AM, Rupp S, Hipler UC, Hube B, Skerka C, Zipfel PF. The pH-regulated antigen 1 of Candida albicans binds the human complement inhibitor C4b-binding protein and mediates fungal complement evasion. J Biol Chem. 2011 Mar 11;286(10):8021-8029. PMID:21212281 doi:10.1074/jbc.M110.130138
- ↑ Soloviev DA, Jawhara S, Fonzi WA. Regulation of innate immune response to Candida albicans infections by αMβ2-Pra1p interaction. Infect Immun. 2011 Apr;79(4):1546-58. PMID:21245270 doi:10.1128/IAI.00650-10
- ↑ Losse J, Svobodová E, Heyken A, Hube B, Zipfel PF, Józsi M. Role of pH-regulated antigen 1 of Candida albicans in the fungal recognition and antifungal response of human neutrophils. Mol Immunol. 2011 Sep;48(15-16):2135-43. PMID:21820180 doi:10.1016/j.molimm.2011.07.007
- ↑ Karkowska-Kuleta J, Kedracka-Krok S, Rapala-Kozik M, Kamysz W, Bielinska S, Karafova A, Kozik A. Molecular determinants of the interaction between human high molecular weight kininogen and Candida albicans cell wall: Identification of kininogen-binding proteins on fungal cell wall and mapping the cell wall-binding regions on kininogen molecule. Peptides. 2011 Dec;32(12):2488-96. PMID:22074954 doi:10.1016/j.peptides.2011.10.021
- ↑ Citiulo F, Jacobsen ID, Miramón P, Schild L, Brunke S, Zipfel P, Brock M, Hube B, Wilson D. Candida albicans scavenges host zinc via Pra1 during endothelial invasion. PLoS Pathog. 2012;8(6):e1002777. PMID:22761575 doi:10.1371/journal.ppat.1002777
- ↑ Jawhara S, Pluskota E, Verbovetskiy D, Skomorovska-Prokvolit O, Plow EF, Soloviev DA. Integrin αXβ₂ is a leukocyte receptor for Candida albicans and is essential for protection against fungal infections. J Immunol. 2012 Sep 1;189(5):2468-77. PMID:22844116 doi:10.4049/jimmunol.1200524
- ↑ Sentandreu M, Elorza MV, Sentandreu R, Fonzi WA. Cloning and characterization of PRA1, a gene encoding a novel pH-regulated antigen of Candida albicans. J Bacteriol. 1998 Jan;180(2):282-9. PMID:9440517 doi:10.1128/JB.180.2.282-289.1998
- ↑ Nore A, Roselletti E, Chakraborty T, Särkkä N, Perera RL, Wilson D, Syrjänen JL. Structural insights into mechanisms of zinc scavenging by the Candida albicans zincophore Pra1. Nat Commun. 2025 Nov 28;16(1):10753. PMID:41315346 doi:10.1038/s41467-025-65782-0
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