Cell Chem Biol
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria. Electronic address:
Published: June 2020
With more than 450 members, the solute carrier (SLC) group of proteins represents the largest class of transporters encoded in the human genome. Their several-pass transmembrane domain structure and hydrophobicity contribute to the orphan status of many SLCs, devoid of known cargos or chemical inhibitors. We report that SLC proteins belonging to different families and subcellular compartments are amenable to induced degradation by heterobifunctional ligands. Engineering endogenous alleles via the degradation tag (dTAG) technology enabled chemical control of abundance of the transporter protein, SLC38A2. Moreover, we report the design of d9A-2, a chimeric compound engaging several members of the SLC9 family and leading to their degradation. d9A-2 impairs cellular pH homeostasis and promotes cell death in a range of cancer cell lines. These findings open the era of SLC-targeting chimeric degraders and demonstrate potential access of multi-pass transmembrane proteins of different subcellular localizations to the chemically exploitable degradation machinery.
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http://dx.doi.org/10.1016/j.chembiol.2020.04.003 | DOI Listing |
Sci Rep
January 2025
Osaka Medical and Pharmaceutical University, 4-20-1, Nasahara, Takatsuki, 569-1094, Osaka, Japan.
Recent advances in the clinical development of oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) and small interfering RNAs, have attracted attention as promising therapeutic modalities for genetic and intractable diseases. These oligonucleotide therapeutics exert their efficacy by binding to target RNAs present within cells; however, the mechanisms underlying their cellular uptake, especially their passage through membranes, remain largely unclear. In the nematode, Caenorhabditis elegans, the multi-pass transmembrane protein, SID-1, is involved in the cellular uptake of double-stranded RNAs.
View Article and Find Full Text PDFRes Sq
October 2024
Institute of Precision Medicine, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Plasma membrane integrity is vital not only for cell survival but also nearly all aspects of cell functioning1. Mechanical stress can cause plasma membrane damage2, but it is not known whether there are large molecules (proteins) that control plasma membrane integrity. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible mechanical strain to adherent cells.
View Article and Find Full Text PDFbioRxiv
July 2024
Dept. of Chemistry and Chemical Biology, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, New York, 12180 USA.
The Solute Carrier (SLC) superfamily of integral membrane proteins function to transport a wide array of solutes across the plasma and organelle membranes. SLC proteins also function as important drug transporters and as viral receptors. Despite being classified as a single superfamily, SLC proteins do not share a single common fold classification; however, most belong to multi-pass transmembrane helical protein fold families.
View Article and Find Full Text PDFHGG Adv
October 2024
University Brest, Inserm, EFS, UMR 1078, GGB, 29200 Brest, France; CHU de Brest, 29200 Brest, France; Laboratory of Excellence GR-Ex, 75015 Paris, France. Electronic address:
Heterozygous mutations in SLC40A1, encoding a multi-pass membrane protein of the major facilitator superfamily known as ferroportin 1 (FPN1), are responsible for two distinct hereditary iron-overload diseases: ferroportin disease, which is associated with reduced FPN1 activity (i.e., decrease in cellular iron export), and SLC40A1-related hemochromatosis, which is associated with abnormally high FPN1 activity (i.
View Article and Find Full Text PDFMol Cell
April 2024
Department of Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA; Center for Mitochondrial Medicine, University of Texas Health San Antonio, San Antonio, TX 78229, USA. Electronic address:
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