Article

Conservation in Aspergillus fumigatus of pH-signaling seven transmembrane domain and arrestin proteins, and implications for drug discovery

Section of Microbiology, Faculty of Medicine, Imperial College London, London, UK.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 12/2012; 1273(1):35-43. DOI: 10.1111/j.1749-6632.2012.06814.x
Source: PubMed

ABSTRACT Adaptation to extracellular pH is a major challenge to fungal pathogens that infect mammalian hosts. Among pH responses mounted by diverse fungal pathogens there is a high degree of molecular conservation. This, coupled with the absence of such signaling pathways in mammalian cells, suggests that this crucial fungal survival mechanism might provide a useful means of limiting a broad spectrum of infectious fungal growth. PacC/Rim signaling converts extracellular cues, perceived by the fungal cell at extremes of ambient pH, into a cellular signal moderating the activation and/or derepression of multiple pH-sensitive gene functions including enzymes, permeases, and transporters. Signal transduction via the fungal PacC/Rim pathway involves a seven transmembrane domain (7TMD) receptor-arrestin protein complex. This review will discuss, with particular attention to Aspergillus fumigatus (the major mold pathogen of humans), the conservation of PacC/Rim signal reception proteins, and protein domains, required for tolerance of pH change, and pathogenicity, and the significance of such molecules as targets for interventive therapies.

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    • "Subsequent translocation of the truncated PacC protein, from cytoplasm to nucleus, permits alkaline adaptation via differential expression of genes required to enable growth under alkaline extracellular conditions (Tilburn et al., 1995; Mingot et al., 1999, 2001; Espeso and Arst, 2000; Espeso et al., 2000). In A. fumigatus the amino acid residues crucial for PalH and PalF interaction are conserved, and in split-ubiquitin analyses the proteins enter into close proximity (Bertuzzi and Bignell, 2011; Bignell, 2012). We have also recently demonstrated the requirement for A. fumigatus PalH for murine infection (Bertuzzi et al., in preparation). "
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