Phosphatase Subfamily Slingshot

Phosphatase Classification: Fold CC1: Superfamily CC1: Family DSP: Subfamily Slingshot

Slingshot, a subfamily conserved in holozoan but lost in nematodes, regulates cofilin phosphorylation with LIMK kinase subfamily.

Evolution

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Slingshot is found across holozoa, but absent from nematodes.

Domain

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Slingshot has three domains: A domain (1-124), B domain (125-308), phosphatase domain (309-450) and Serine-enriched region close to C-terminus (positioned by human SSH1). A domain is required for the F-actin-mediated activation of SSH1 and therefore may mediate slingshot binding to actin. F-actin increased the cofilin-phosphatase activity of SSH1 more than 1200-fold. B domain and phosphatase domain are indispensable for phosphorylated-cofilin (P-cofilin) binding. The phosphatase domain alone is sufficient for the phosphatase activity toward p-nitrophenyl phosphate (pNPP), indicating that the SSH-N domain is not essential for the basal phosphatase activity of SSH1 [1]. Besides, motifs LHKACE (amino acids 185–190) in the B domain and LKRSHS (amino acids 973–978) in the S domain of SSH1 may also contribute to F-actin binding [2].

Note: As annotated by Pfam, there is a DEK C terminal domain from 251 to 303, which is part of B domain.

Function

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Slingshots dephosphorylate cofilin, a ubiquitous actin-binding factor required for the reorganization of actin filaments, in Drosophila and human [3] (see here for cofilin function). In human, there are three members in slingshot subfamily. They are significantly different in subcellular distribution, F-actin-binding activity, specific phosphatase activity and expression patterns, which suggests that they have related but distinct functions in various cellular and developmental events [4].

In addition to substrate cofilin, Coronin 1B has been proposed to be slingshot's substrate [5].

Regulation

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Slingshot is regulated by protein kinase D (PKD), which phosphorylates serines 937 and 978 and therefore regulates human SSH1 subcellular localization by binding of 14-3-3 proteins [6]. PKD also phosphorylates serine 402 that impedes phosphatase activity of human SSH1 [7]. 14-3-3zeta/tau heterodimers regulate Slingshot activity in migrating keratinocytes [8]. SSH1L is activated by its release from a regulatory complex with 14-3-3zeta protein through the redox-mediated oxidation of 14-3-3zeta [9].

References

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