The fungal metabolite brefeldin A disrupts protein secretion and causes the redistribution of the Golgi complex to the endoplasmic reticulum. Previously we isolated six genes that, when present in multiple copies, confer brefeldin A resistance to wild type Schizosaccharomyces pombe. Here we describe the characterization of one of these genes, hba1. This gene encodes an essential protein that shares homology with the mammalian protein RanBP1 and the protein encoded by the Saccharomyces cerevisiae gene YRB1 and contains a peptide motif present in several proteins found within the nuclear pore complex. The protein encoded by hba1 is localized to the nucleus, and it was determined that this protein is phosphorylated in vivo. The characterization of hba1 thus demonstrates a novel mechanism of drug resistance in S. pombe.
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http://dx.doi.org/10.1074/jbc.271.15.9166 | DOI Listing |
Genes (Basel)
November 2024
Neurology Unit, Department of Translational Medicine, Maggiore Della Carità Hospital, University of Piemonte Orientale, 28100 Novara, Italy.
Background/objectives: Axonal Charcot-Marie-Tooth disease type 2 (CMT2) accounts for 24% of Hereditary Motor/Sensory Peripheral Neuropathies. CMT2 type GG, due to four distinct heterozygous mutations in the Golgi brefeldin A resistant guanine nucleotide exchange factor 1 () gene (OMIM 606483), was described in seven cases from four unrelated families with autosomal dominant inheritance. It is characterized by slowly progressive distal muscle weakness and atrophy, primarily affecting the lower limbs.
View Article and Find Full Text PDFBiochemistry
December 2024
Interdisciplinary Life Sciences Graduate Program, The University of Texas at Austin, Austin, Texas 78712, United States.
Understanding the factors that contribute to specificity of protein-protein interactions allows for design of orthosteric small molecules. Within this environment, a small molecule requires both structural and electrostatic complementarity. While the structural contribution to protein-drug-protein specificity is well characterized, electrostatic contributions require more study.
View Article and Find Full Text PDFJ Cell Sci
December 2024
Division of Cell Signalling & Immunology and School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK.
AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular functions in response to changes in energy availability. However, whether AMPK activity is spatially regulated, and the implications for cell function, have been unclear. We now report that AMPK associates with the Golgi, and that its activation by two specific pharmacological activators leads to Golgi fragmentation similar to that caused by the antibiotic Golgicide A, an inhibitor of Golgi-specific Brefeldin A resistance factor-1 (GBF1), a guanine nucleotide exchange factor that targets ADP-ribosylation factor 1 (ARF1).
View Article and Find Full Text PDFFEBS Lett
November 2024
Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan.
Iqsec1 (IQ motif and Sec7 domain-containing protein 1), also known as BRAG2 (Brefeldin A-resistant Arf-GEF 2), is a guanine nucleotide exchange factor that regulates membrane trafficking, cytoskeletal organization, and signal transduction by activating class II and III ADP-ribosylation factors. To investigate the physiological role of Iqsec1 at the whole animal level, we generated Iqsec1-deficient mice using CRISPR/Cas9-mediated gene editing. Nearly all Iqsec1 mice (99%) exhibited embryonic lethality with severe growth retardation.
View Article and Find Full Text PDFMar Life Sci Technol
August 2024
Key Laboratory of Marine Drugs, the Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003 China.
Unlabelled: As one of the common malignancies that threaten human life, bladder cancer occurs frequently with a high mortality rate in the world, due to its invasion, recurrence and drug resistance. Natural products from marine microorganisms are becoming the hotspots in discovery of new candidate drug entities, especially in the area of cancer. Brefeldin A (BFA) is a natural Arf-GEFs inhibitor, but due to the low aqueous solubility, strong toxicity, and poor bioavailability, it is urgent to conduct structural optimization research.
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