The {SH3} domain of Caskin1 binds to lysophosphatidic acid suggesting a direct role for the lipid in intracellular signaling

TitleThe {SH3} domain of Caskin1 binds to lysophosphatidic acid suggesting a direct role for the lipid in intracellular signaling
Publication TypeJournal Article
Year of Publication2017
AuthorsKoprivanacz, K, Tőke, O, Besztercei, B, Juhász, T, Radnai, L, Merő, B, Mihály, J, Péter, M, Balogh, G, Vígh, L, Buday, L, Liliom, K
JournalCellular Signalling
Volume32
Pagination66 - 75
ISSN0898-6568
Keywordsproline-rich motif
Abstract

Abstract Src homology 3 or {SH3} domains constitute one of the most common protein domains in signal transduction, generally characterized by their binding to proline-rich sequences on interacting signaling proteins. Caskin1, a scaffold protein regulating cortical actin filaments, enriched in neural synapses in mammals, has an atypical {SH3} domain. Key aromatic residues necessary for ligand binding that are present in canonical {SH3} domains are missing from Caskin1 SH3. In concordance, proline-rich interacting partner could not be identified yet. Based on previous reports that several {SH3} domains are able to bind phospholipids, we sought for lipid interacting partners of the {SH3} domain of human Caskin1. We investigated the signaling-born lysophospholipid mediators, such as lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) as potential binding partners for this {SH3} domain. These lipid mediators as first messengers activate G protein-coupled receptors. They also exert several G protein-coupled receptor-independent functions but their intracellular target proteins are mostly unknown. Here we provide evidence that the {SH3} domain of human Caskin1 selectively binds to {LPA} in vitro. The binding strength and stoichiometry depend on the association-state of the lipid, with nanomolar affinity to LPA-containing membraneous surfaces. The amino acids involved in the interaction are located in a β-strand structure and are distinct from those corresponding to the canonical proline-rich ligand-binding groove in the {SH3} domain of Src kinase. Our results suggest that the {SH3} domain of human Caskin1 is a lipid-binding domain rather than a proline-rich motif interacting domain.

URL//www.sciencedirect.com/science/article/pii/S0898656817300268
DOI10.1016/j.cellsig.2017.01.019