Mutual homeostasis of charged proteins
bioRxiv (Cold Spring Harbor Laboratory)(2023)
摘要
Abstract Protein dosage is regulated to maintain cellular homeostasis and health. The dosage of proteins containing disordered low complexity domains (LCDs) must be particularly well-controlled to prevent aberrant disease, yet no mechanism to maintain homeostasis has been identified 1, 2 . Here we report a mutual homeostatic mechanism that controls the concentration of such proteins, termed ’interstasis’, in which proteins with similar LCDs co-regulate their combined dosage through collective negative feedback. We focused on the mechanism that exploits the fundamental multivalency of GA-rich RNA regions that encode charged LCDs, including those with arginine-enriched mixed charge domains (R-MCDs). Modest variations in the abundance of an R-MCD protein change the properties of nuclear speckles, a protein-RNA condensate, selectively trapping multivalent GA-rich mRNAs to promote their nuclear retention. This interstasis depends on conserved codon biases, shared by amniotes, which enhance the multivalency of GA-rich regions encoding charged LCDs. The threshold of interstasis is modulated by CLK kinases, which affect the nuclear speckle localisation of proteins such as TRA2B, key binder of GA-rich RNAs. Notably, many classes of LCDs are encoded by RNA regions containing multivalency-enhancing codon biases, each preferentially bound by specific proteins, suggesting that interstasis might co-regulate many classes of functionally related LCD-containing proteins through dose-sensitivity of various types of protein-RNA condensates.
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关键词
mutual homeostasis,proteins
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