title: Delineating distinct heme-scavenging and -binding functions of domains in MF6p/helminth defense molecule (HDM) proteins from parasitic flatworms.
abstract: MF6p/FhHDM-1 is a small protein secreted by the parasitic flatworm (trematode)Fasciola hepaticathat belongs to a broad family of heme-binding proteins (MF6p/helminth defense molecules (HDMs)). MF6p/HDMs are of interest for understanding heme homeostasis in trematodes and as potential targets for the development of new flukicides. Moreover, interest in these molecules has also increased because of their immunomodulatory properties. Here we have extended our previous findings on the mechanism of MF6p/HDM-heme interactions and mapped the protein regions required for heme binding and for other biological functions. Our data revealed that MF6p/FhHDM-1 forms high-molecular-weight complexes when associated with heme and that these complexes are reorganized by a stacking procedure to form fibril-like and granular nanostructures. Furthermore, we showed that MF6p/FhHDM-1 is a transitory heme-binding protein as protein·heme complexes can be disrupted by contact with an apoprotein (e.g.apomyoglobin) with higher affinity for heme. We also demonstrated that (i) the heme-binding region is located in the MF6p/FhHDM-1 C-terminal moiety, which also inhibits the peroxidase-like activity of heme, and (ii) MF6p/HDMs from other trematodes, such asOpisthorchis viverriniandParagonimus westermani, also bind heme. Finally, we observed that the N-terminal, but not the C-terminal, moiety of MF6p/HDMs has a predicted structural analogy with cell-penetrating peptides and that both the entire protein and the peptide corresponding to the N-terminal moiety of MF6p/FhHDM-1 interactin vitrowith cell membranes in hemin-preconditioned erythrocytes. Our findings suggest that MF6p/HDMs can transport heme in trematodes and thereby shield the parasite from the harmful effects of heme.
authors.affiliation: From the Laboratorio de Parasitología, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Martínez-Sernández
authors.affiliation: the Laboratorio de Parasitología, Centro de Investigaciones Agrarias de Mabegondo, Instituto Galego da Calidade Alimentaria (INGACAL), 15318 Abegondo, A Coruña, Spain, and.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Mezo
authors.affiliation: the Laboratorio de Parasitología, Centro de Investigaciones Agrarias de Mabegondo, Instituto Galego da Calidade Alimentaria (INGACAL), 15318 Abegondo, A Coruña, Spain, and.
authors.forename: Marta
authors.initials: M
authors.lastname: González-Warleta
authors.affiliation: the Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: María J
authors.initials: MJ
authors.lastname: Perteguer
authors.affiliation: the Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Gárate
authors.affiliation: From the Laboratorio de Parasitología, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Romarís
authors.affiliation: From the Laboratorio de Parasitología, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain, fm.ubeira@usc.es.
authors.forename: Florencio M
authors.initials: FM
authors.lastname: Ubeira
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D005210:Fasciola hepatica / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015801:Helminth Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D009891:Opisthorchis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D048492:Paragonimus westermani / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains
chemical_list: D002352:Carrier Proteins; D015801:Helminth Proteins; D006418:Heme
keywords: Fasciola; MF6p/FhHDM-1; MF6p/HDM; cell-penetrating peptide (CPP); fluke; heme; homeostasis; oligomerization; parasite; trematode