Abstract
Saposins are small proteins implicated in trafficking and loading of lipids onto Cluster of Differentiation 1 (CD1) receptor proteins that in turn present lipid antigens to T cells and a variety of T-cell receptors, thus playing a crucial role in innate and adaptive immune responses in humans. Despite their low sequence identity, the four types of human saposins share a similar folding pattern consisting of four helices linked by three conserved disulfide bridges. However, their lipid-binding abilities as well as their activities in extracting, transporting and loading onto CD1 molecules a variety of sphingo- and phospholipids in biological membranes display two striking characteristics: a strong pH-dependence and a structural change between a compact, closed conformation and an open conformation. In this work, we present a comparative computational study of structural, electrostatic, and dynamic features of human saposins based upon their available experimental structures. By means of structural alignments, surface analyses, calculation of pH-dependent protonation states, Poisson-Boltzmann electrostatic potentials, and molecular dynamics simulations at three pH values representative of biological media where saposins fulfill their function, our results shed light into their intrinsic features. The similarities and differences in this class of proteins depend on tiny variations of local structural details that allow saposins to be key players in triggering responses in the human immune system.
Highlights
Antigen presentation molecules are key players in innate and adaptive immune responses.Whereas the major histocompatibility complex class I and II proteins present peptide antigens toT cells, Cluster of Differentiation 1 (CD1) molecules can bind a great diversity of lipidic ligands and are responsible for presenting lipid antigens to T cells and a variety of T-cell receptors [1,2,3].Exogenous lipids are transported to different endocytic compartments according to their length after incorporation into the membrane
Saposins share with other small proteins involved in lipid transport such as nonspecific lipid transfer proteins, a fold consisting of four α-helices linked by disulfide bonds
Lipid-binding proteins usually have a number of polar and/or charged residues in the proximity of their hydrophobic sites. In spite of this structural similarity to non-specific lipid transfer proteins (nsLTPs), our study indicates that saposins apparently make no use of internal cavities to harbor and transport lipids, a result consistent with the available evidence on their lipid-binding features
Summary
Antigen presentation molecules are key players in innate and adaptive immune responses.Whereas the major histocompatibility complex class I and II proteins present peptide antigens toT cells, Cluster of Differentiation 1 (CD1) molecules can bind a great diversity of lipidic ligands and are responsible for presenting lipid antigens to T cells and a variety of T-cell receptors [1,2,3].Exogenous lipids are transported to different endocytic compartments according to their length after incorporation into the membrane. Antigen presentation molecules are key players in innate and adaptive immune responses. T cells, Cluster of Differentiation 1 (CD1) molecules can bind a great diversity of lipidic ligands and are responsible for presenting lipid antigens to T cells and a variety of T-cell receptors [1,2,3]. Exogenous lipids are transported to different endocytic compartments according to their length after incorporation into the membrane. CD1 molecules traffic through those compartments sampling antigens in the endocytic pathway. Saposins (for “sphingolipid activator proteins”, or SAPs) are small (8–11 kDa), acidic, non-enzymatic, heat-stable, protease-resistant, lipid-binding proteins known to assist in CD1 lipid loading in endosomal compartments [4,5]. Four saposins named A, B, C, and D are generated through proteolytic cleavage from a single precursor protein, prosaposin, that is Molecules 2018, 23, 422; doi:10.3390/molecules23020422 www.mdpi.com/journal/molecules
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