Phosphatase Subfamily Slingshot

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

Slingshot regulates cofilin phosphorylation with LIMK kinase subfamily.

Evolution

Slingshot is found across holozoa, but absent from nematodes.

Domain

Slingshot has three domains defined experimentally: A domain (1-124), B domain (125-308), phosphatase domain (309-450) and Serine-enriched region close to C-terminus (numbering from human SSH1) [1]. The B domain includes the Pfam domain DEK_C. The 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. The 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) [1]. The motifs LHKACE (AA 185–190) in the B domain and LKRSHS (AA 973–978) in the S domain of SSH1 may also contribute to F-actin binding [2].

Function

Slingshot dephosphorylates cofilin, a ubiquitous actin-binding factor required for the reorganization of actin filaments, in Drosophila and human [3] (see here for cofilin function). The three human slingshot genes are significantly different in subcellular distribution, actin-binding activity, phosphatase activity and expression patterns [4]. Coronin 1B has also been proposed to be a slingshot substrate [5].

Regulation

Slingshot is regulated by protein kinase D (PKD), which phosphorylates serines 937 and 978 and regulates human SSH1 subcellular localization by binding of 14-3-3 proteins [6]. PKD also phosphorylates serine 402 to inhibit phosphatase activity [7]. 14-3-3zeta/tau heterodimers regulate Slingshot activity in migrating keratinocytes [8]. SSH1 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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