A short guided tour through functional and structural features of saposin-like proteins

Abstract

SAPLIPs (saposin-like proteins) are a diverse family of lipid-interacting proteins that have various and only partly understood, but nevertheless essential, cellular functions. Their existence is conserved in phylogenetically most distant organisms, such as primitive protozoa and mammals. Owing to their remarkable sequence variability, a common mechanism for their actions is not known. Some shared principles beyond their diversity have become evident by analysis of known three-dimensional structures. Whereas lipid interaction is the basis for their functions, the special cellular tasks are often defined by interaction partners other than lipids. Based on recent findings, this review summarizes phylogenetic relations, function and structural features of the members of this family.

Figure 1. Schematic depiction of the three main activities of SAPLIPs

(A) Membrane targeting by the SAPLIP domain. (B) Presentation of lipids as substrate for an independent enzyme, either by extraction from the membrane or by disturbance of the well-packed lipid order. (C) Membrane permeabilization by perturbation owing to single molecules or by pore-formation of oligomeric proteins. Red triangle, SAPLIP domain; green circle, enzymatic domain; blue circle, independent enzyme acting on lipids (arrows).

Figure 2. Diversity and conserved features of SAPLIP sequences

(A) Unrooted tree of the experimentally characterized SAPLIPs mentioned in the text. The early divergence of the single sequences reflects their diversity. AP-like, amoebapore-like. (B) The corresponding sequence logo reveals conserved features. The invariable cysteine residues are displayed in yellow, hydrophobic amino acid residues are coloured green, polar residues are purple, negatively charged ones are red, positively charged ones are blue and others are grey.

Figure 3. Structures of SAPLIPs

(A) Superposition of NK-lysin (red; Protein Data Bank code 1NKL), granulysin (orange; Protein Data Bank code 1L9L) and saposin C (yellow; Protein Data Bank code 1M12). (B) Structure of amoebapore A (Protein Data Bank code 1OF9), the orientations of helices 1 and 5 are twisted compared with (A). (C) Structure of a saposin B dimer (Protein Data Bank code 1N69) showing the open conformation.

Figure 4. Sequence alignment of selected SAPLIPs

Negatively charged amino acid residues are coloured red, positively charged ones are blue and aromatic residues are displayed in green. (A) Proteins with antimicrobial activity. The position of the α-helices of NK-lysin is shown at the top. AP-like, amoebapore-like; E. caballus, Equus caballus. (B) Saposin isoforms from different species: Homo, Homo sapiens; Bos, Bos taurus; Mus, Mus musculus; Gallus, Gallus gallus; Xenopus, Xenopus laevis; Danio, Danio rerio.