Identification of key features required for efficient S-acylation and plasma membrane targeting of Sprouty-2

Locatelli, Carolina and Lemonidis, Kimon and Salaun, Christine and Tomkinson, Nicholas C. O. and Chamberlain, Luke H. (2020) Identification of key features required for efficient S-acylation and plasma membrane targeting of Sprouty-2. Journal of Cell Science, 133 (21). jcs249664. ISSN 0021-9533 (

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Sprouty-2 is an important regulator of growth factor signalling and a tumour suppressor protein. The defining feature of this protein is a cysteine-rich domain (CRD) that contains twenty-six cysteines and is modified by S-acylation. In this study, we show that the CRD of Sprouty-2 is differentially modified by S-acyltransferase enzymes. The high specificity/low activity zDHHC17 enzyme mediated restricted S-acylation of Sprouty-2, and cysteines-265/268 were identified as key targets of this enzyme. In contrast, the low specificity/high activity zDHHC3/zDHHC7 enzymes mediated more expansive modification of the Sprouty-2 CRD. Nevertheless, S-acylation by all enzymes enhanced Sprouty-2 expression, suggesting that S-acylation stabilises this protein. In addition, we identified two charged residues (aspartate-214 and lysine-223), present on opposite faces of a predicted alpha helix in the CRD, which are essential for S-acylation of Sprouty-2. Interestingly, mutations that perturbed S-acylation also led to a loss of plasma membrane localisation of Sprouty-2 in PC12 cells. This study provides insight into the mechanisms and outcomes of Sprouty-2 S-acylation, and highlights distinct patterns of S-acylation mediated by different classes of zDHHC enzymes.


Locatelli, Carolina, Lemonidis, Kimon ORCID logoORCID:, Salaun, Christine ORCID logoORCID:, Tomkinson, Nicholas C. O. ORCID logoORCID: and Chamberlain, Luke H. ORCID logoORCID:;