| From the Human Genenome Project
http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/hfe.shtml |
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Official Gene Symbol: HFE
Alternate Symbol: HLA-H Name of Gene Product: hereditary hemochromatosis protein Locus: 6p21.3 The HFE gene is found in region 21.3 on the short (p) arm of human chromosome 6. Size: The HFE gene’s 7 coding regions (exons) are scattered over about 10,000 base pairs of genomic DNA. Exons translated into the HFE protein are interspersed with segments of noncoding DNA (introns). After transcription, introns are spliced out and exons are pieced together to form an mRNA transcript about 2700 bp long. The mRNA is then translated into the 348-amino acid sequence of the hereditary hemochromatosis protein [1,2,3]. Mutations in the HFE gene can result in hereditary hemochromatosis (HH). |
Protein Function
The HFE protein is a transmembrane protein expressed in intestinal and liver cells; it works in conjunction with another small protein called beta-2-microglobulin to regulate iron uptake [4]. Although homologous to other major histocompatibility complex (MHC) class I proteins that present antigens to killer T cells, the HFE protein appears to have no immunological function [5]. The HFE protein is an interesting example of how homology is not always an indicator of protein function.
Sequence Exercise
The “mRNA” sequences obtained from databases such as NCBI’s GenBank are actually complementary DNA (cDNA) sequences generated from mRNA transcripts extracted from cells. Genomic DNA sequences of eukaryotic organisms contain coding segments (exons) interspersed with noncoding segments (introns). During transcription, introns are spliced out and exons are pieced together to form messenger RNA (mRNA). In addition to containing nucleotides that are translated into the amino acid sequence of a particular protein, mRNA also contains untranslated regions upstream and downstream of the coding sequence. Intron-free cDNA sequences synthesized from mRNA also comprise these untranslated regions.
Use the Table of Standard Genetic Code to find the initiation codon (ATG) and next nine codons in the HFE nucleotide sequence shown below. The first 10 amino acids of the hereditary hemochromatosis (HH) protein sequence are as follows:
M G P R A R P A L L
1 ggggacactg gatcacctag tgtttcacaa gcaggtacct tctgctgtag gagagagaga
61 actaaagttc tgaaagacct gttgcttttc accaggaagt tttactgggc atctcctgag
121 cctaggcaat agctgtaggg tgacttctgg agccatcccc gtttccccgc cccccaaaag
181 aagcggagat ttaacgggga cgtgcggcca gagctgggga aatgggcccg cgagccaggc
241 cggcgcttct cctcctgatg cttttgcaga ccgcggtcct gcaggggcgc ttgctgcgt
Nucleotide sequence taken from NCBI RefSeq record NM_000410
The answer is at the bottom of this page.
| Protein Structure
HFE protein consists of extracellular alpha-1 and alpha-2 domains that sit on top of the immunoglobulin-like alpha-3 domain, which spans the cell membrane and binds a separate protein called beta-2-microglobulin. The alpha-1 and apha-2 domains interact with the transferrin receptor, another transmembrane protein that plays a very important role in iron uptake and regulation [6]. |
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Figure 1 shows backbone structures of two HFE protein molecules. Blue and green chains represent HFE proteins, and smaller aqua and gold chains represent molecules of beta-2 microglobulin. Purple residues indicate where cysteine 282 is located in each HFE chain. A mutation at cysteine 282 is a common cause of hereditary hemochromatosis. |
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Common Disease-Causing Mutation
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The most common mutation responsible for hereditary hemochromatosis is the substitution of tyrosine for cysteine at the 282nd amino acid position in the protein sequence (C282Y mutation). The cysteine residue at this position is part of a disulfide bond that forms a loop in the alpha-3 domain of the HFE protein.
When cysteine 282 is lost, the disulfide bond cannot be formed and the HFE protein’s alpha-3 domain is no longer able to complex with beta-2-microglobulin, which serves as a stabilization factor. As a result, the mutated HFE protein is degraded before it has a chance to be incorporated into the cell membrane. Cells become iron-overloaded when there is no HFE to negatively regulate the iron flow into the cell’s cytoplasm [4]. Over time, iron overload in these cells can damage tissues and organs, leading to symptoms and complications associated with HH. |
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Additional Resources
HFE Protein Sequence HFE Protein Structure
HFE Mutation Resources Other HFE Web resources
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