Phosphorylation of Candida glabrata ATP-binding Cassette Transporter Cdr1p Regulates Drug Efflux Activity and ATPase Stability
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Fungal ATP-binding cassette transporter regulation was investigated using Candida glabrata Cdr1p and Pdh1p expressed in Saccharomyces cerevisiae. Rephosphorylation of Pdh1p and Cdr1p was protein kinase A inhibitor-sensitive but responded differentially to Tpk isoforms, stressors, and glucose concentration. Cdr1p Ser(307), which borders the nucleotide binding domain 1 ABC signature motif, and Ser(484), near the membrane, were dephosphorylated on glucose depletion and independently rephosphorylated during glucose exposure or under stress. The S484A enzyme retained half the wild type ATPase activity without affecting azole resistance, but the S307A enzyme was unstable to plasma membrane isolation. Studies of pump function suggested conformational interaction between Ser(484) and Ser(307). An S307A/S484A double mutant, which failed to efflux the Cdr1p substrate rhodamine 6G, had a fluconazole susceptibility 4-fold greater than the Cdr1p expressing strain, twice that of the S307A mutant, but 64-fold less than the control null strain. Stable intragenic suppressors indicative of homodimer nucleotide binding domain 1-nucleotide binding domain 1 interactions partially restored rhodamine 6G pumping and increased fluconazole and rhodamine 6G resistance in the S307A/S484A mutant. Nucleotide binding domain 1 of Cdr1p is a sensor of important physiological stimuli.
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R6G is specifically extruded by CgCdr1 in an ATP-dependent manner.
“which is specifically extruded by CgCdr1 in an ATP-dependent manner (52).”
From The Rho1 GTPase-activating protein CgBem2 is required for survival of azole stress in Candida glabrata (2011) · cites this paper as [52]
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- Authors
- Wada, S.-I., Tanabe, K., Yamazaki, A., Niimi, M., Uehara, Y., Niimi, K., Lamping, E., Cannon, R. D., & Monk, B. C.
- Affiliations
- National Institute of Infectious Diseases (JP)
- University of Otago (NZ)
- Corresponding author
- Niimi, Masakazu
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 280
- Issue
- 1
- Pages
- 94-103
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2064688740
- Cited by
- 39
- References
- 28
- Citations by year
- 2026: 1 · 2024: 1 · 2021: 1 · 2019: 3 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 2 · 2012: 1
- FWCI
- 1.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Health Research Council of New Zealand
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- Cdr1p, ABC transporters, Candida glabrata, phosphorylation, drug efflux, protein kinase A, glucose depletion, azole resistance, fluconazole susceptibility, rhodamine 6G, NBD1, intragenic suppressors, plasma membrane, antifungal resistance
- MeSH terms
- Adenosine Triphosphatases, Antifungal Agents, Biological Transport, Enzyme Stability, Fungal Proteins, Membrane Proteins, Mutation, Phosphorylation, ATP-Binding Cassette Transporters, Drug Resistance, Multiple, Fungal, Membrane Transport Proteins, Saccharomyces cerevisiae Proteins, Candida glabrata
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