Abstract
SLURP-1 is a member of three-finger toxin-like proteins. Their characteristic feature is a set of three beta strands extruding from hydrophobic core stabilized by disulfide bonds. Each beta-strand carries a flexible loop, which is responsible for recognition. SLURP-1 was recently shown to act as an endogenous growth regulator of keratinocytes and tumor suppressor by reducing cell migration and invasion by antagonizing the pro-malignant effects of nicotine. This effect is achieved through allosteric interaction with alpha7 nicotinic acetylcholine receptors (alpha-7 nAChRs) in an antagonist-like manner. Moreover, this interaction is unaffected by several well-known agents specifically alpha-bungarotoxin. In this work, we carry out the conformational analysis of the SLURP-1 by a microsecond-long full-atom explicit solvent molecular dynamics simulations followed by clustering, to identify representative states. To achieve this timescale we employed a GPU-accelerated version of GROMACS modeling package. To avoid human bias in clustering we used a non-parametric clustering algorithm Affinity Propagation adapted for biomolecules and HPC environments. Then, we applied protein-protein molecular docking of the ten most massive clusters to alpha7-nAChRs in order to test if structural variability can affect binding. Docking simulations revealed the unusual binding mode of one of the minor SLURP-1 conformations.
Highlights
Three-finger proteins of the Ly6 family have multiple functions across the organism: from lignd-binding domains of growth factors receptors to regulation of nicotinic receptor expression and function in the brain (Lynx1)
Most mammalian Ly6 proteins have a GPI anchor at the C-terminus attaching them to the membrane while others do not have it and are secreted. Among the latter is SLURP-1 functioning as a water-soluble paracrine/autocrine messenger molecule which binds nicotinic acetylcholine receptors and regulates keratinocyte growth and angiogenesis
Such properties of SLURP-1 make it a valuable object to study as an endogenous cholinergic ligand similar to snake venom neurotoxins that played a crucial role in the nAChR research for decades [8, 10]
Summary
Three-finger proteins of the Ly6 family have multiple functions across the organism: from lignd-binding domains of growth factors receptors (myostatin receptor) to regulation of nicotinic receptor (nAChR) expression and function in the brain (Lynx). Most mammalian Ly6 proteins have a GPI anchor at the C-terminus attaching them to the membrane while others do not have it and are secreted Among the latter is SLURP-1 functioning as a water-soluble paracrine/autocrine messenger molecule which binds nicotinic acetylcholine receptors and regulates keratinocyte growth and angiogenesis. Such properties of SLURP-1 make it a valuable object to study as an endogenous cholinergic ligand similar to snake venom neurotoxins that played a crucial role in the nAChR research for decades [8, 10]. SLURP-1 fusion constructs bearing unnatural tags and labels show properties drastically different from those described for recombinant SLURP-1 which has only one additional N-terminal Met residue (PDB ID: 2MUO). No experimental spatial structure of fusion SLURP-1 proteins
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