Haptoglobin-related protein

Last updated
HPR
Identifiers
Aliases HPR , A-259H10.2, HP
External IDs OMIM: 140210 HomoloGene: 122206 GeneCards: HPR
Orthologs
SpeciesHumanMouse
Entrez

3250

n/a

Ensembl

ENSG00000261701

n/a

UniProt

P00739

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RefSeq (mRNA)

NM_020995
NM_001384360

n/a

RefSeq (protein)

NP_066275

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Location (UCSC) Chr 16: 72.06 – 72.08 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Haptoglobin-related protein (Hpr) is a serum protein that binds to haemoglobin of red blood cells and is present only in primates. [3] It acts as a molecule of innate immunity in association with apolipoprotein L1 (ApoL 1)-containing high-density lipoprotein (HDL) particles. [4] In humans, together with related serum protein, haptoglobin, it acts as a cell-killing agent as part of the trypanolytic factor against the protozoan parasite Trypanosoma brucei thereby providing natural resistance to African sleeping sickness. [5] It is produced from the gene HPR that is located on the long arm of chromosome 16 within the HP (for haptoglobin) gene cluster. [6]

Contents

History

Haptoglobin was discovered as a "plasma substance" in 1938 by French biochemists Max-Fernand Jayle and Michel Polonovski. [7] [8] The gene (later denoted as HP or Hp) was identified by British biochemist Oliver Smithies and his mentor, Canadian geneticist Norma Ford Walker in 1956. [9] [10] Smithies and Walker discovered that the gene could exist in two allelic autosomal genes, Hp1and Hp2. [11] Additional allele and associated genes were subsequently identified. [12]

In 1983, Italian geneticist Riccardo Cortese and his team, led by Giovanni Raugei, sequenced the human Hp gene and discovered that there is a closely related gene in the vicinity. [13] As they reported: "Southern blot analysis provides evidence for the presence of more than one haptoglobin gene per haploid genome and confirms that there is restriction site polymorphism at this locus." [14] The next year, Smithies team, then at the University of Wisconsin, US, identified the same new gene and gave the name Hpr (for haptoglobin-related). [15] The protein, Hpr, was determined by New York University Medical Center scientists Madhavi Muranjan, Victor Nussenzweig and Stephen Tomlinson in 1998. [16]

Structure

Hpr is 45-kDa in molecular size. It is structurally similar to haptoglobin with over 90% amino acid identity but in lesser concentration in the blood. [16] Like haptoglobin, it is composed of α- and β-chain which are connected through a disulfide bond. [17] It lacks a glycosylation site and a cysteine involved in inter-α-chain bonding that are present in haptoglobin. Haptoglobin has either 1 (Hp1 genotype) or 2 (Hp2 genotype) of such cysteines. The α-chain of Hpr contains a hydrophobic signal peptide, which is absent in haptoglobin. The signal peptide makes Hpr associated with ApoL 1. [4]

The HPR gene originated from duplication of the HP gene and is present at 2.2 kilobase pairs downstream of the HP gene on the long arm of chromosome 16 in humans. [6] [16] HPR is 94% similar in DNA sequence to HP gene. [5] The gene is also present in apes and Old World monkeys in which it is created from a gene triplication (additional HP gene is present) during early evolution of the primate group. [3] Some humans have additional copy of HPR gene. [5] The gene product has 28-amino acid differences, 16 of which occur in the β chain. HPR has longer intron, 9.5 kilobase pairs compared to 1.3 kilobase pairs of that of haptoglobin. It contains a retrovirus-like element that is not found in haptoglobin. [18]

Function

Haptoglobin is known to be a high affinity-binding protein for haemoglobin during red blood cell destruction (haemolysis). Since Hpr is an accessory protein, it was initially believed that it that does not bind haemoglobin. [16] However, an experiment in 2006 showed that it binds to haemoglobin with same affinity as haptoglobin. [4] Unlike haptoglobin which binds to the scavenger receptor CD163, a protein on macrophages that is critical for eliminating bacterial infection, [19] Hpr has no affinity for the receptor indicating that its primary role is different. [16] [20]

The major function of Hpr is protection from infection with Trypanosoma brucei to provide natural resistance to African sleeping sickness. [5] Together with haptolglobin and apoliproproteins, it makes up a trypanolytic factor TLF 1 in the blood of primates that can kill invading the animal strain of T. brucei (specifically T. b. brucei). [21] However, chimpanzees have mutated Hpr so that their serum cannot kill T. b. brucei. [22] The human strains, T. b. rhodesiense and T. b. gambiense have acquired resistance to TLF indicating an evolutionary arms race between primates and the protozoan parasite. [23] Hpr is also involved in TLF 2 in which its function is not yet understood. [5]

Related Research Articles

<span class="mw-page-title-main">Haptoglobin</span> Mammalian protein found in Homo sapiens

Haptoglobin is the protein that in humans is encoded by the HP gene. In blood plasma, haptoglobin binds with high affinity to free hemoglobin released from erythrocytes, and thereby inhibits its deleterious oxidative activity. Compared to Hp, hemopexin binds to free heme. The haptoglobin-hemoglobin complex will then be removed by the reticuloendothelial system.

<span class="mw-page-title-main">Serum protein electrophoresis</span> Laboratory test

Serum protein electrophoresis is a laboratory test that examines specific proteins in the blood called globulins. The most common indications for a serum protein electrophoresis test are to diagnose or monitor multiple myeloma, a monoclonal gammopathy of uncertain significance (MGUS), or further investigate a discrepancy between a low albumin and a relatively high total protein. Unexplained bone pain, anemia, proteinuria, chronic kidney disease, and hypercalcemia are also signs of multiple myeloma, and indications for SPE. Blood must first be collected, usually into an airtight vial or syringe. Electrophoresis is a laboratory technique in which the blood serum is applied to either an acetate membrane soaked in a liquid buffer, or to a buffered agarose gel matrix, or into liquid in a capillary tube, and exposed to an electric current to separate the serum protein components into five major fractions by size and electrical charge: serum albumin, alpha-1 globulins, alpha-2 globulins, beta 1 and 2 globulins, and gamma globulins.

alpha-2-Macroglobulin Large plasma protein found in the blood

α2-Macroglobulin (α2M) or alpha-2-macroglobulin is a large plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it is encoded by the A2M gene.

Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood proteins act as enzymes, complement components, protease inhibitors or kinin precursors. Contrary to popular belief, haemoglobin is not a blood protein, as it is carried within red blood cells, rather than in the blood serum.

<i>Trypanosoma</i> Genus of parasitic flagellate protist in the Kinetoplastea class

Trypanosoma is a genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. Trypanosoma is part of the phylum Euglenozoa. The name is derived from the Greek trypano- (borer) and soma (body) because of their corkscrew-like motion. Most trypanosomes are heteroxenous and most are transmitted via a vector. The majority of species are transmitted by blood-feeding invertebrates, but there are different mechanisms among the varying species. Trypanosoma equiperdum is spread between horses and other equine species by sexual contact. They are generally found in the intestine of their invertebrate host, but normally occupy the bloodstream or an intracellular environment in the vertebrate host.

<span class="mw-page-title-main">Protein S</span>

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation.

<i>Trypanosoma brucei</i> Species of protozoan parasite

Trypanosoma brucei is a species of parasitic kinetoplastid belonging to the genus Trypanosoma that is present in sub-Saharan Africa. Unlike other protozoan parasites that normally infect blood and tissue cells, it is exclusively extracellular and inhabits the blood plasma and body fluids. It causes deadly vector-borne diseases: African trypanosomiasis or sleeping sickness in humans, and animal trypanosomiasis or nagana in cattle and horses. It is a species complex grouped into three subspecies: T. b. brucei, T. b. gambiense and T. b. rhodesiense. The first is a parasite of non-human mammals and causes nagana, while the latter two are zoonotic infecting both humans and animals and cause African trypanosomiasis.

<span class="mw-page-title-main">Major basic protein</span>

Eosinophil major basic protein, often shortened to major basic protein is encoded in humans by the PRG2 gene.

<span class="mw-page-title-main">Hemopexin</span>

Hemopexin, also known as beta-1B-glycoprotein, is a glycoprotein that in humans is encoded by the HPX gene and belongs to the hemopexin family of proteins. Hemopexin is the plasma protein with the highest binding affinity for heme.

<span class="mw-page-title-main">Integrin beta 3</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Alternative oxidase</span>

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<span class="mw-page-title-main">CD163</span> Protein-coding gene in the species Homo sapiens

CD163 is a protein that in humans is encoded by the CD163 gene. CD163 is the high affinity scavenger receptor for the hemoglobin-haptoglobin complex and in the absence of haptoglobin - with lower affinity - for hemoglobin alone. It also is a marker of cells from the monocyte/macrophage lineage. CD163 functions as innate immune sensor for gram-positive and gram-negative bacteria. The receptor was discovered in 1987.

<span class="mw-page-title-main">Glycodelin</span> Mammalian protein found in Homo sapiens

Glycodelin(GD) also known as human placental protein-14 (PP-14)progestogen-associated endometrial protein (PAEP) or pregnancy-associated endometrial alpha-2 globulin is a glycoprotein that inhibits cell immune function and plays an essential role in the pregnancy process. In humans is encoded by the PAEP gene.

<span class="mw-page-title-main">PTPN12</span> Protein-coding gene in the species Homo sapiens

Tyrosine-protein phosphatase non-receptor type 12 is an enzyme that in humans is encoded by the PTPN12 gene.

<span class="mw-page-title-main">Apolipoprotein L1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">RBP3</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Variant surface glycoprotein</span>

Variant surface glycoprotein (VSG) is a ~60kDa protein which densely packs the cell surface of protozoan parasites belonging to the genus Trypanosoma. This genus is notable for their cell surface proteins. They were first isolated from Trypanosoma brucei in 1975 by George Cross. VSG allows the trypanosomatid parasites to evade the mammalian host's immune system by extensive antigenic variation. They form a 12–15 nm surface coat. VSG dimers make up ~90% of all cell surface protein and ~10% of total cell protein. For this reason, these proteins are highly immunogenic and an immune response raised against a specific VSG coat will rapidly kill trypanosomes expressing this variant. However, with each cell division there is a possibility that the progeny will switch expression to change the VSG that is being expressed. VSG has no prescribed biochemical activity.

GT198 is a human oncogene located within the BRCA1 locus at chromosome 17q21. It encodes protein product named GT198, Hop2 or TBPIP. The GT198 gene is found to be mutated with its protein overexpressed in human cancers including breast and ovarian cancers.

Barbara Hyde Bowman was an American biologist, geneticist, and educator who was known for her research in human blood proteins. Her work characterized variants of globins, the family of proteins responsible for transporting blood in oxygen, and in 1984, Oliver Smithies and she showed that variations in haptoglobins were due to polymorphisms in the HP gene.

Keith Roland Matthews,, , is a British cell biologist and parasitologist, currently Professor of Parasite Biology in the School of Biological Sciences at the University of Edinburgh. His research focuses on African trypanosomes, which cause human sleeping sickness and the equivalent cattle disease nagana.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000261701 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 McEvoy SM, Maeda N (1988-10-25). "Complex events in the evolution of the haptoglobin gene cluster in primates". The Journal of Biological Chemistry. 263 (30): 15740–15747. doi: 10.1016/S0021-9258(19)37650-1 . ISSN   0021-9258. PMID   3170608.
  4. 1 2 3 Nielsen MJ, Petersen SV, Jacobsen C, Oxvig C, Rees D, Møller HJ, et al. (2006-10-15). "Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein". Blood. 108 (8): 2846–2849. doi: 10.1182/blood-2006-05-022327 . ISSN   0006-4971. PMID   16778136.
  5. 1 2 3 4 5 Hardwick RJ, Ménard A, Sironi M, Milet J, Garcia A, Sese C, et al. (2014). "Haptoglobin (HP) and Haptoglobin-related protein (HPR) copy number variation, natural selection, and trypanosomiasis". Human Genetics. 133 (1): 69–83. doi:10.1007/s00439-013-1352-x. ISSN   1432-1203. PMC   3898332 . PMID   24005574.
  6. 1 2 Koda Y, Soejima M, Yoshioka N, Kimura H (1998). "The haptoglobin-gene deletion responsible for anhaptoglobinemia". American Journal of Human Genetics. 62 (2): 245–252. doi:10.1086/301701. ISSN   0002-9297. PMC   1376878 . PMID   9463309.
  7. ↑ Shih AW, McFarlane A, Verhovsek M (2014). "Haptoglobin testing in hemolysis: measurement and interpretation". American Journal of Hematology. 89 (4): 443–447. doi: 10.1002/ajh.23623 . ISSN   1096-8652. PMID   24809098.
  8. ↑ "Haptoglobins". New England Journal of Medicine. 266 (11): 569–570. 1962-03-15. doi:10.1056/NEJM196203152661115. ISSN   0028-4793.
  9. ↑ Smithies O, Walker NF (1956-09-29). "Notation for serum-protein groups and the genes controlling their inheritance". Nature. 178 (4535): 694–695. Bibcode:1956Natur.178..694S. doi:10.1038/178694a0. ISSN   0028-0836. PMID   13369501.
  10. ↑ Mäkelä O, Eriksson A, Lehtovaara R (2008-08-06). "On the inheritance of the haptoglobin serum groups". Acta Genetica et Statistica Medica. 9 (2): 149–166. doi:10.1159/000151092. ISSN   0365-2785. JSTOR   45103594. PMID   14420139.
  11. ↑ Giblett ER (1964-01-01). "Variant Haptoglobin Phenotypes". Cold Spring Harbor Symposia on Quantitative Biology. 29: 321–326. doi:10.1101/SQB.1964.029.01.034. ISSN   0091-7451. PMID   14278478.
  12. ↑ Van der straten A, Cabezón T, Resibois A, Bollen A (1985-01-01), Peeters H (ed.), Structure of the Human Haptoglobin Pseudogene, Protides of the Biological Fluids, vol. 33, Elsevier, pp. 151–155, doi:10.1016/B978-0-08-033215-4.50039-X, ISBN   978-0-08-033215-4 , retrieved 2024-01-26
  13. ↑ Bensi G, Raugei G, Klefenz H, Cortese R (1985). "Structure and expression of the human haptoglobin locus". The EMBO Journal. 4 (1): 119–126. doi:10.1002/j.1460-2075.1985.tb02325.x. PMC   554159 . PMID   4018023.
  14. ↑ Raugei G, Bensi G, Colantuoni V, Romano V, Santoro C, Costanzo F, et al. (1983-09-10). "Sequence of human haptoglobin cDNA: evidence that the alpha and beta subunits are coded by the same mRNA". Nucleic Acids Research. 11 (17): 5811–5819. doi:10.1093/nar/11.17.5811. ISSN   0305-1048. PMC   326319 . PMID   6310515.
  15. ↑ Maeda N, Yang F, Barnett DR, Bowman BH, Smithies O (1984). "Duplication within the haptoglobin Hp2 gene". Nature. 309 (5964): 131–135. Bibcode:1984Natur.309..131M. doi:10.1038/309131a0. ISSN   1476-4687. PMID   6325933.
  16. 1 2 3 4 5 Muranjan M, Nussenzweig V, Tomlinson S (1998-02-13). "Characterization of the human serum trypanosome toxin, haptoglobin-related protein". The Journal of Biological Chemistry. 273 (7): 3884–3887. doi: 10.1074/jbc.273.7.3884 . ISSN   0021-9258. PMID   9461571.
  17. ↑ Imrie HJ, Fowkes FJ, Migot-Nabias F, Luty AJ, Deloron P, Hajduk SL, et al. (2012). "Individual variation in levels of haptoglobin-related protein in children from Gabon". PLOS ONE. 7 (11): e49816. Bibcode:2012PLoSO...749816I. doi: 10.1371/journal.pone.0049816 . ISSN   1932-6203. PMC   3502254 . PMID   23185445.
  18. ↑ Maeda N (1985-06-10). "Nucleotide sequence of the haptoglobin and haptoglobin-related gene pair. The haptoglobin-related gene contains a retrovirus-like element". The Journal of Biological Chemistry. 260 (11): 6698–6709. doi: 10.1016/S0021-9258(18)88836-6 . ISSN   0021-9258. PMID   2987228.
  19. ↑ Fabriek BO, van Bruggen R, Deng DM, Ligtenberg AJ, Nazmi K, Schornagel K, et al. (January 2009). "The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria" (PDF). Blood. 113 (4): 887–92. doi:10.1182/blood-2008-07-167064. PMID   18849484. S2CID   4811741.
  20. ↑ Skytthe MK, Sørensen AL, Hennig D, Sandberg MB, Rasmussen LM, Højrup P, et al. (2022-10-03). "Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes". Scandinavian Journal of Clinical and Laboratory Investigation. 82 (6): 461–466. doi:10.1080/00365513.2022.2122076. ISSN   0036-5513. PMID   36129375. S2CID   252406321.
  21. ↑ Drain J, Bishop JR, Hajduk SL (2001-08-10). "Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes". The Journal of Biological Chemistry. 276 (32): 30254–30260. doi: 10.1074/jbc.M010198200 . ISSN   0021-9258. PMID   11352898.
  22. ↑ Seed JR, Sechelski JB, Loomis MR (1990). "A survey for a trypanocidal factor in primate sera". The Journal of Protozoology. 37 (5): 393–400. doi:10.1111/j.1550-7408.1990.tb01163.x. ISSN   0022-3921. PMID   2120433.
  23. ↑ Capewell P, Cooper A, Clucas C, Weir W, Macleod A (2015). "A co-evolutionary arms race: trypanosomes shaping the human genome, humans shaping the trypanosome genome". Parasitology. 142 (Suppl 1): S108–119. doi:10.1017/S0031182014000602. ISSN   1469-8161. PMC   4413828 . PMID   25656360.
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