IMR Press / FBL / Volume 4 / Issue 4 / DOI: 10.2741/dawson

Frontiers in Bioscience-Landmark (FBL) is published by IMR Press from Volume 26 Issue 5 (2021). Previous articles were published by another publisher on a subscription basis, and they are hosted by IMR Press on imrpress.com as a courtesy and upon agreement with Frontiers in Bioscience.

Open Access Article
Molecular mechanisms underlying inhibition of protein phosphatases by marine toxins
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1 MRC Protein Structure and Function Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7
Academic Editor:Norbert Berndt
Front. Biosci. (Landmark Ed) 1999, 4(4), 646–658; https://doi.org/10.2741/dawson
Published: 1 October 1999
(This article belongs to the Special Issue Cellular functions of protein phosphatases)
Abstract

The protein serine/threonine phosphatases constitute a unique class of enzymes that are critical regulatory enzymes as they must counteract the activities of thousands of protein kinases in human cells. Uncontrolled inhibition of phosphatase activity by toxic inhibitors can lead to widespread catastrophic effects. Over the past decade, a number of natural product toxins have been identified which specifically and potently inhibit protein phosphatase-1 and -2A. Among these are the cyanobacteria-derived cyclic heptapeptide microcystin-LR and the polyether fatty acid okadaic acid from dinoflagellate sources. The molecular mechanism of the potent inhibition of protein phosphatase-1 by these toxins is becoming clear through insights gathered from diverse sources. These include: 1. Comparison of structural variants of the toxins, 2. Delineating the structural differences between protein phosphatase-1 and -2A accounting for their differing sensitivity to okadaic acid, 3. Determination of the crystal structure of protein phosphatase-1 with microcystin-LR bound and, most recently, 4. Mutagenesis of protein phosphatase-1. Taken together, these data point to a common binding site on protein phosphatase-1 for okadaic acid and microcystin-LR. However, the details of these data suggest that each toxin binds to the common site in a subtly different way, relying on common structural interactions to different degrees. Finally, the insights derived from protein phosphatase-1 may help explain different sensitivities of other protein serine/threonine phosphatases to toxin inhibition due to the high degree of structural conservation among many members of this enzyme family.

Keywords
Signal Transduction
Mutagenesis
Crystallography
PPP phosphatases
Okadaic Acid
Microcystin-LR
Protein Phosphatase-1
Protein Phosphatase2A
Protein Phosphatase-2B
Marine Toxins
Review
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