The double lives of phosphatases of regenerating liver: A structural view of their catalytic and noncatalytic activities

Abstract

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The Integral Membrane Protein ZMPSTE24 Protects Cells from SARS-CoV-2 Spike-Mediated Pseudovirus Infection and Syncytia Formation

“…Examples of enzymes which moonlight to also perform nonenzymatic functions are known. One example is the phosphatase of regenerating liver (PRL), which has catalytic phosphatase activity for certain phosphorylated substrates but also has a non-catalytic role in regulating the integral membrane magnesium transporter CNNM ( 58 , 59 ). Structural analyses revealed that CNNM mimics a PRL substrate and binds near residues in PRL required for catalysis.…”

Structural insights into regulation of TRPM7 divalent cation uptake by the small GTPase ARL15

“…In addition to ARL15, CNNM CBS-pair domains bind PRLs with low nanomolar affinity (Gulerez et al ., 2016). Binding is mediated by an aspartic acid that inserts into the phosphatase catalytic site, mimicking a phosphoprotein substrate (Gehring et al, 2022; Gimenez-Mascarell et al ., 2017; Gulerez et al ., 2016). While the binding sites overlap, a CNNM dimer could simultaneously bind ARL15 and PRLs using separate CBS-pair domains.…”

Burst kinetics and CNNM binding are evolutionarily conserved properties of phosphatases of regenerating liver

“…Despite their broad distribution and importance in cancer and development, PRLs are poorly understood ( 15 ). They are highly potent oncogenes implicated in tumorigenesis and metastasis but have no confirmed substrates.…”

“…A phosphorous-sulfur intermediate occurs in all cysteine-based phosphatases ( 11 , 12 ), but the intermediate is unusually long-lived in PRLs ( 10 , 13 , 14 ). The accumulation of phosphorylated enzyme leads to the phenomenon of burst kinetics, which is characterized by a fast initial rate of catalysis followed by a slow steady-state rate ( 10 , 15 ). In cells, PRLs are largely found in the phosphorylated form and the level of phosphorylation varies as a function of magnesium availability ( 13 , 14 ).…”