Perforin-2/Mpeg1 and other pore-forming proteins throughout evolution

Abstract

Development of the ancient innate immune system required not only a mechanism to recognize foreign organisms from self but also to destroy them. Pore-forming proteins containing the membrane attack complex Perforin domain were one of the first triumphs of an innate immune system needing to eliminate microbes and virally infected cells. Membrane attack complex of complement and Perforin domain proteins is unique from other immune effector molecules in that the mechanism of attack is strictly physical and unspecific. The large water-filled holes created by membrane attack complex of complement and Perforin domain pore formation allow access for additional effectors to complete the destruction of the foreign organism via chemical or enzymatic attack. Perforin-2/macrophage-expressed protein 1 is one of the oldest membrane attack complexes of complement and Perforin domain protein involved in immune defense, and it is still functional today in vertebrates. Here, we trace the impact of Perforin-2/macrophage-expressed protein 1 from the earliest multicellular organisms to modern vertebrates, as well as review the development of other membrane attack complexes of complement and Perforin domain member proteins.

Keywords: MACPF; bacteria; complement.

Figure 1.. Proposed orientation of Perforin-2 within cells.

(A) Orientation of Perforin-2 within an endosome. (B) Orientation of Perforin-2 on the extracellular surface of the cell. P-2 D, Conserved Perforin-2 domain within all organisms that express this protein; TM, transmembrane domain; Cyto, cytoplasmic domain.

Figure 2.. Evolutionary clustering of Perforin-2 MACPF domains.

The MACPF domain of Perforin-2 clusters into 3 distinct groups. The 1st is that of sponges, the 2nd is invertebrates, and the 3rd is vertebrates. S. domuncula, Suberites domuncula; M. musculus, Mus musculus; R. norvegicus, Rattus norvegicus; H. sapiens, Homo sapiens; P. paniscus, Pan paniscus; D. rerio, Danio rerio; C. gigas, Crassostrea gigas; H. rufescens, Haliotis rufescens; H. corrugata, Haliotis corrugata; H. diversicolor supertexta, Haliotis diversicolor supertexta; H. midae, Haliotis midae.

Figure 3.. Phylogenetic tree of full-length Perforin-2 protein throughout evolution with known duplications.

B. taurus, Bos taurus; B. bison, Bison bison; F. catus, Felis catus; A. melanoleuca, Ailuropoda melanoleuca; S. boliviensis, Saimiri boliviensis; C. angolensis, Cordylus angolensis; P. abelii, Pongo abelii; T. rubripes, Takifugu rubripes; P. reticulata, Poecilia reticulata; L. crocea, Larimichthys crocea; A. mexicanus, Astyanax mexicanus; O. hannah, Ophiophagus hannah; H. leucocephalus, Haliaeetus leucocephalus; S. partitus, Stegastes partitus; H. discus, Haliotis discus.

Figure 4.. Schematic of C9 of complement and Perforin-1 compared with Perforin-2.

Unlike Perforin-2, which is membrane bound, both C9 of complement and Perforin-1 are soluble proteins. EGF, Epidermal growth factor; C2, calcium-dependent plasma membrane-binding domain.

Figure 5.. Schematic illustrating the hypothetical model of Perforin-2 trafficking to intra- or attached extracellular foreign organisms and ensuing bactericidal activity.