Secreted Phospholipases A2 - not just Enzymes: Revisited

Abstract

Secreted phospholipases A₂ (sPLA₂s) participate in a very broad spectrum of biological processes through their enzymatic activity and as ligands for membrane and soluble receptors. The physiological roles of sPLA₂s as enzymes have been very well described, while their functions as ligands are still poorly known. Since the last overview of sPLA₂-binding proteins (sPLA₂-BPs) 10 years ago, several important discoveries have occurred in this area. New and more sensitive analytical tools have enabled the discovery of additional sPLA₂-BPs, which are presented and critically discussed here. The structural diversity of sPLA₂-BPs reveals sPLA₂s as very promiscuous proteins, and we offer some structural explanations for this nature that makes these proteins evolutionarily highly advantageous. Three areas of physiological engagement of sPLA₂-BPs have appeared most clearly: cellular transport and signalling, and regulation of the enzymatic activity of sPLA₂s. Due to the multifunctionality of sPLA₂s, they appear to be exceptional pharmacological targets. We reveal the potential to exploit interactions of sPLA₂s with other proteins in medical terms, for the development of original diagnostic and therapeutic procedures. We conclude this survey by suggesting the priority questions that need to be answered.

Keywords: Secreted phospholipase A2; binding protein; cell transport; phospholipase activity regulation; promiscuity; signalling.

Figure 1

Distinct structural elements present in more than one type of sPLA₂-BP. (A) CRD (PDB ID: 6JLI) and the CRD-like fold are structural elements found in M-type sPLA₂Rs, SP-A and α-PLIs. (B) The EF-hand Ca²⁺-binding motif (PDB ID: 1CLL) is found in CaM, crocalbin and TCBP-49, which all bind sPLA₂s. (C) The Ig-like domain (PDB ID: 2X1X) is found in VEGFRs and DM64. To date, only the CRD has been experimentally demonstrated to be a sPLA₂-binding structure. Red, α-helices; violet, β-sheets; grey, loops. The Figure was prepared using UCSF Chimera v1.15.

Figure 2

Secreted PLA₂s are ligands of proteins that are structurally very diverse. The three-dimensional models, generated by molecular docking, are showing complexes between the sPLA₂ Atx and CaM (green, PDB ID: 1CLL) (A), Atx and FXa (blue, PDB ID: 2BOH) (B), CB_b and ΔF508NBD1 of CFTR (PDB ID: 1XMJ) (C), Atx and PDI (purple/pink, PDB ID: 4EL1) (D), and between the sPLA₂ vurtoxin and nAChR (grey, PDB ID: 2BG9) (E). Centre: The sPLA₂ Atx, showing its main structural elements. Red, interfacial binding surface; yellow, disulphide bonds; violet, C-terminal region. Note that the sPLA₂s interact with these different sPLA₂-BPs in very different ways; i.e., they have multiple protein binding sites, as is characteristic of promiscuous proteins. The Figure was prepared by adaptation of Figures from Kovačič et al. (2010) (A), Faure and Saul (2011) (B), Faure et al. (2016) (C), Oberčkal et al. (2015) (D) and Vulfius et al. (2014) (E), using PyMOL.

Figure 3

Pathophysiological implications of binding of sPLA₂s to sPLA₂-BPs. Physiological and/or pathological effects of sPLA₂s (red) are also the consequence of their binding to sPLA₂-BPs. (A) By binding to sPLA₂-BPs (blue/cyan), sPLA₂s can be translocated to specific intracellular compartments, such as the endoplasmic reticulum (a), cytosol (b), nucleus (c), mitochondria (d) or lysosomes (e). In each of these compartments, they can act as enzymes or ligands for receptors, or they can undergo proteolytic degradation in the lysosome. (B) As ligands for receptors, sPLA₂s have been specifically implicated in molecular signalling through decreased (1) or increased (2) permeabilities of certain ion channels, inhibition (3) or activation (4) of activities of receptor tyrosine kinases, modulation of activities of GPCR (5), interference in integrin-mediated functions (6), attenuation of ATP production (7) and inhibition of blood coagulation, at different stages (8, 9, 10). (C) Binding of sPLA₂ to a sPLA₂-BP might inhibit or potentiate phospholipolytic activity. The Figure was created with BioRender.com.