@article{86a9b8e7a5b54a62a370793002ed74a6,
title = "A somatic multiple myeloma mutation unravels a mechanism of oligomerization-mediated product inhibition in GGPPS",
abstract = "Protein prenylation plays a critical role in regulating the cellular localization of small GTPases and is essential for multiple myeloma (MM) pathology. Geranylgeranyl diphosphate synthase (GGPPS), producing a key prenylation moiety, exists in a dimeric or hexameric form, depending on the species. However, the functional significance of this oligomerization remains unclear. Using crystallography, mass spectrometry, and fluorescence spectroscopy, we show that the GGPPSR235C mutant{\textemdash}found in the widely studied MM cell line RPMI-8226{\textemdash}exhibits weakened inter-dimer interactions, reduced hexamer stability, and increased apparent substrate affinity and product release kinetics. These effects are even more pronounced in a dimeric mutant, GGPPSY246D, demonstrating that interdimer interactions within the hexamer help stabilize a lid region over the active site, thereby stabilizing product binding in an inhibitory conformation. Together, these findings reveal that hexamerization regulates GGPPS activity through product inhibition and underscore the importance of cell line selection and characterization in drug discovery efforts.",
keywords = "GGPPS, multiple myeloma, oligomerization, structure{\textendash}function",
author = "Ruba Yehia and Porta{\v s}ikov{\'a}, \{Jasm{\'i}na M{\'a}ria\} and \{Mor Yosef\}, Rut and Benny Da'adoosh and Alan K{\'a}dek and Petr Man and Moshe Giladi and Yoni Haitin",
note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). The FEBS Journal published by John Wiley \& Sons Ltd on behalf of Federation of European Biochemical Societies.",
year = "2025",
month = nov,
doi = "10.1111/febs.70181",
language = "אנגלית",
volume = "292",
pages = "5802--5817",
journal = "FEBS Journal",
issn = "1742-464X",
publisher = "John Wiley and Sons Inc.",
number = "21",
}