变构调节
GTP'
核苷酸
生物化学
酶
鸟嘌呤核苷酸交换因子
鸟嘌呤
化学
鸟苷二磷酸
生物
细胞生物学
鸟苷三磷酸
GTP酶
基因
作者
David Fernández‐Justel,Rafael López Núñez,Jaime Martı́n-Benito,David Jimeno,Adrián González-López,Eva Soriano,José Luis Revuelta,Rubén M. Buey
标识
DOI:10.1016/j.jmb.2019.01.020
摘要
Inosine 5′-monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in the de novo GTP biosynthetic pathway and plays essential roles in cell proliferation. As a clinical target, IMPDH has been studied for decades, but it has only been within the last years that we are starting to understand the complexity of the mechanisms of its physiological regulation. Here, we report structural and functional insights into how adenine and guanine nucleotides control a conformational switch that modulates the assembly of the two human IMPDH enzymes into cytoophidia and allosterically regulates their catalytic activity. In vitro reconstituted micron-length cytoophidia-like structures show catalytic activity comparable to unassembled IMPDH but, in turn, are more resistant to GTP/GDP allosteric inhibition. Therefore, IMPDH cytoophidia formation facilitates the accumulation of high levels of guanine nucleotides when the cell requires it. Finally, we demonstrate that most of the IMPDH retinopathy-associated mutations abrogate GTP/GDP-induced allosteric inhibition and alter cytoophidia dynamics.
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