Ubiquitin is an indispensable protein of eukaryotic origin with an extraordinarily high degree of sequence conservation. It is used to tag proteins post-translationally and the process of ubiquitination regulates the activity of the modified proteins or drives them for degradation. Double mutations produce varied effects in proteins, depending on the structural relationship of the mutated residues, their role in the overall structure and functions of a protein. Six double mutants derived from the ubiquitin mutant UbEP42, namely S20F-A46S, S20F-L50P, S20F-I61T, A46S-L50P, A46S-I61T, and L50P-I61T, have been studied here to understand how they influence the ubiquitination related functions, by analysing their growth and viability, Cdc28 levels, K-48 linked polyubiquitination, UFD pathway, lysosomal degradation, endosomal sorting, survival under heat, and antibiotic stresses. The double mutation L50P-I61T is the most detrimental, followed by S20F-I61T and A46S-I61T. The double mutations studied here, in general, make cells more sensitive than the wild type to one or the other stress. However, the excessive negative effects of L50P and I61T are compensated under certain conditions by S20F and A46S mutations. The competitive inhibition produced by these substitutions could be used to manage certain ubiquitination associated diseases.
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