Heme and FLVCR-related transporter families SLC48 and SLC49

Abstract

Heme is critical for a variety of cellular processes, but excess intracellular heme may result in oxidative stress and membrane injury. Feline leukemia virus subgroup C receptor (FLVCR1), a member of the SLC49 family of four paralogous genes, is a cell surface heme exporter, essential for erythropoiesis and systemic iron homeostasis. Disruption of FLVCR1 function blocks development of erythroid progenitors, likely due to heme toxicity. Mutations of SLC49A1 encoding FLVCR1 are noted in patients with a rare neurodegenerative disorder: posterior column ataxia with retinitis pigmentosa. FLVCR2 is highly homologous to FLVCR1 and may function as a cellular heme importer. Mutations of SLC49A2 encoding FLVCR2 are observed in Fowler syndrome, a rare proliferative vascular disorder of the brain. The functions of the remaining members of the SLC49 family, MFSD7 and DIRC2 (encoded by the SLC49A3 and SLC49A4 genes), are unknown, although the latter is implicated in hereditary renal carcinomas. SLC48A1 (heme responsive gene-1, HRG-1), the sole member of the SLC48 family, is associated with the endosome and appears to transport heme from the endosome into the cytosol.

Fig. 1

(A)Predicted topology of FLVCR1. The protein is predicted to have 12 TMD with both N- and C-termini in the cytosol. The tyrosine-based, di-leucine, and PDZ domain–binding motifs are shown. By analogy to other heme-binding proteins, H145, Y153, and H198 residues are predicted to constitute a heme-binding pocket. A potential N-linked glycosylation signal (NIS) is located in exofacial loop 3. Four mutations identified in patients with PCARP, N121D, C192R, A241T, and G493R are shown in TMD 1, 3, 5, and 12, respectively. Note that the predicted topology of the other SLC49 members—FLVCR2, SLC49A3/MFD7, and SLC49A4/DIRC2—is similar. (B) Predicted topology of HRG-1. The transporter is predicted to have 4 TMD (Rajagopal et al., 2008). The residues H56 and H100 and the YAHRY motif in the C-terminus are predicted to be important for heme transport.

Fig. 2

Cellular localization of SLC48 and SLC49 family members. SLC49A1/FLVCR1 and SLC49A2/FLVCR2 are plasma membrane proteins. SLC49A4/DIRC2 is predominantly located in the lysosome where it may exist as two half-transporters. The protein can also be found on the cell surface. The cellular location of SLC49A3/MFSD7 is unknown. SLC48A1/HRG-1 is located primarily in the endosome-lysosomal compartment. Alternative predicted topologies for SLC48A1 are shown (O’Callaghan et al., 2009; Rajagopal et al., 2008), see section 3.1. for details.