RRC ID 46541
Author Yuan X, Protchenko O, Philpott CC, Hamza I.
Title Topologically conserved residues direct heme transport in HRG-1-related proteins.
Journal J Biol Chem
Abstract Caenorhabditis elegans and human HRG-1-related proteins are conserved, membrane-bound permeases that bind and translocate heme in metazoan cells via a currently uncharacterized mechanism. Here, we show that cellular import of heme by HRG-1-related proteins from worms and humans requires strategically located amino acids that are topologically conserved across species. We exploit a heme synthesis-defective Saccharomyces cerevisiae mutant to model the heme auxotrophy of C. elegans and demonstrate that, under heme-deplete conditions, the endosomal CeHRG-1 requires both a specific histidine in the predicted second transmembrane domain (TMD2) and the FARKY motif in the C terminus tail for heme transport. By contrast, the plasma membrane CeHRG-4 transports heme by utilizing a histidine in the exoplasmic (E2) loop and the FARKY motif. Optimal activity under heme-limiting conditions, however, requires histidine in the E2 loop of CeHRG-1 and tyrosine in TMD2 of CeHRG-4. An analogous system exists in humans, because mutation of the synonymous histidine in TMD2 of hHRG-1 eliminates heme transport activity, implying an evolutionary conserved heme transport mechanism that predates vertebrate origins. Our results support a model in which heme is translocated across membranes facilitated by conserved amino acids positioned on the exoplasmic, cytoplasmic, and transmembrane regions of HRG-1-related proteins. These findings may provide a framework for understanding the structural basis of heme transport in eukaryotes and human parasites, which rely on host heme for survival.
Volume 287(7)
Pages 4914-24
Published 2012-2-10
DOI 10.1074/jbc.M111.326785
PII M111.326785
PMID 22174408
PMC PMC3281596
MeSH Amino Acid Motifs Animals Biological Transport, Active / physiology Caenorhabditis elegans / chemistry Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Carrier Proteins / chemistry Carrier Proteins / genetics Carrier Proteins / metabolism* Heme / metabolism* Hemeproteins / chemistry Hemeproteins / genetics Hemeproteins / metabolism* Humans Models, Biological* Mutation Protein Structure, Tertiary Saccharomyces cerevisiae / chemistry Saccharomyces cerevisiae / genetics Saccharomyces cerevisiae / metabolism
IF 4.106
Times Cited 33
C.elegans tm3199 tm2994