Biology:Haptoglobin-related protein

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Short description: Blood protein in primates

Haptoglobin-related protein (Hpr) is a serum protein that binds to haemoglobin of red blood cells and is present only in primates.[1] It acts as a molecule of innate immunity in association with apolipoprotein L1 (ApoL 1)-containing high-density lipoprotein (HDL) particles.[2] 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.[3] It is produced from the gene HPR that is located on the long arm of chromosome 16 within the HP gene (for haptoglobin) cluster.[4]

History

Haptoglobin was discovered as a "plasma substance" in 1938 by French biochemists Max-Fernand Jayle and Michel Polonovski.[5][6] The gene (later denoted as HP or Hp) was identified British biochemist Oliver Smithies and his mentor, Canadian geneticist Norma Ford Walker in 1956.[7][8] Smithies and Walker discovered that the gene could exist in two allelic autosomal genes, Hp1and Hp2.[9] Additional allele and associated genes were subsequently identified.[10]

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.[11] 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."[12] The next year, Smithies team then at the University of Wisconsin, USA, identified the same new gene and gave the name Hpr (for haptoglobin-related).[13] The protein, Hpr, was determined by New York University Medical Center scientists Madhavi Muranjan, Victor Nussenzweig and Stephen Tomlinson in 1998.[14]

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.[14] Like haptoglobin, it is composed of α- and β-chain which are connected through a disulfide bond.[15] 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.[2]

The HPR gene originated from duplication of the HP gene and is present 2.2 kilobase pairs downstream of the HP gene on the long arm of chromosome 16.[4][14] HPR is 94% similar in DNA sequence to HP gene.[3] HPR gene is also present in apes and Old World monkeys in which it is created by a gene triplication (additional HP gene is present) during early evolution of the primate group.[1] Some humans have additional copy of HPR gene.[3] 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.[16]

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.[14] However, an experiment in 2006 showed that it binds to haemoglobin with same affinity as haptoglobin.[2] Unlike haptoglobin which binds to the scavenger receptor CD163, a protein on macrophages that is critical for eliminating bacterial infection,[17] Hpr has no affinity for the receptor indicating that its primary role is different.[14][18]

The major function of Hpr is protection from infection with Trypanosoma brucei to provide natural resistance to African sleeping sickness.[3] 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).[19] However, chimpanzees have mutated Hpr so that their serum cannot kill T. b. brucei.[20] 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.[21] Hpr is also involved in TLF 2 in which its function is not yet understood.[3]

References

  1. ↑ 1.0 1.1 McEvoy, S. M.; 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. 
  2. ↑ 2.0 2.1 2.2 Nielsen, Marianne Jensby; Petersen, Steen Vang; Jacobsen, Christian; Oxvig, Claus; Rees, David; Møller, Holger Jon; Moestrup, Søren Kragh (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. https://ashpublications.org/blood/article/108/8/2846/22566/Haptoglobin-related-protein-is-a-high-affinity. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Hardwick, Robert J.; Ménard, Anne; Sironi, Manuela; Milet, Jacqueline; Garcia, André; Sese, Claude; Yang, Fengtang; Fu, Beiyuan 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. PMID 24005574. 
  4. ↑ 4.0 4.1 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. PMID 9463309. 
  5. ↑ Shih, Andrew W. Y.; McFarlane, Andrew; Verhovsek, Madeleine (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. https://onlinelibrary.wiley.com/doi/full/10.1002/ajh.23623. 
  6. ↑ "Haptoglobins" (in en). New England Journal of Medicine 266 (11): 569–570. 1962-03-15. doi:10.1056/NEJM196203152661115. ISSN 0028-4793. http://www.nejm.org/doi/abs/10.1056/NEJM196203152661115. 
  7. ↑ Smithies, O.; Walker, N. F. (1956-09-29). "Notation for serum-protein groups and the genes controlling their inheritance". Nature 178 (4535): 694–695. doi:10.1038/178694a0. ISSN 0028-0836. PMID 13369501. https://pubmed.ncbi.nlm.nih.gov/13369501. 
  8. ↑ Mäkelä, O.; Eriksson, A.W.; Lehtovaara, Raimo (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. https://doi.org/10.1159/000151092. 
  9. ↑ Giblett, Eloise R. (1964-01-01). "Variant Haptoglobin Phenotypes" (in en). Cold Spring Harbor Symposia on Quantitative Biology 29: 321–326. doi:10.1101/SQB.1964.029.01.034. ISSN 0091-7451. PMID 14278478. http://symposium.cshlp.org/content/29/321. 
  10. ↑ 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 (Elsevier) 33: pp. 151–155, https://www.sciencedirect.com/science/article/pii/B978008033215450039X, retrieved 2024-01-26 
  11. ↑ Bensi, G.; Raugei, G.; Klefenz, H.; Cortese, R. (1985). "Structure and expression of the human haptoglobin locus." (in en). The EMBO Journal 4 (1): 119–126. doi:10.1002/j.1460-2075.1985.tb02325.x. PMID 4018023. PMC 554159. https://onlinelibrary.wiley.com/doi/10.1002/j.1460-2075.1985.tb02325.x. 
  12. ↑ Raugei, G.; Bensi, G.; Colantuoni, V.; Romano, V.; Santoro, C.; Costanzo, F.; Cortese, R. (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. PMID 6310515. PMC 326319. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC326319/pdf/nar00362-0028.pdf. 
  13. ↑ Maeda, Nobuyo; Yang, Funmei; Barnett, Don R.; Bowman, Barbara H.; Smithies, Oliver (1984). "Duplication within the haptoglobin Hp2 gene" (in en). Nature 309 (5964): 131–135. doi:10.1038/309131a0. ISSN 1476-4687. PMID 6325933. https://www.nature.com/articles/309131a0. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 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. https://www.jbc.org/article/S0021-9258(17)47145-6/fulltext. 
  15. ↑ Imrie, Heather J.; Fowkes, Freya J. I.; Migot-Nabias, Florence; Luty, Adrian J. F.; Deloron, Philippe; Hajduk, Stephen L.; Day, Karen P. (2012). "Individual variation in levels of haptoglobin-related protein in children from Gabon". PLOS ONE 7 (11): e49816. doi:10.1371/journal.pone.0049816. ISSN 1932-6203. PMID 23185445. Bibcode: 2012PLoSO...749816I. 
  16. ↑ 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. 
  17. ↑ "The macrophage scavenger receptor CD163 functions as an innate immune sensor for bacteria". Blood 113 (4): 887–92. January 2009. doi:10.1182/blood-2008-07-167064. PMID 18849484. https://pure.uva.nl/ws/files/1058309/145313_306960.pdf. 
  18. ↑ Skytthe, Maria Kløjgaard; Sørensen, Anna Lahn; Hennig, Dorle; Sandberg, Maria Boysen; Rasmussen, Lars Melholt; Højrup, Peter; Møller, Holger J.; Skjødt, Karsten et al. (2022-10-03). "Haptoglobin-related protein in human plasma correlates to haptoglobin concentrations and phenotypes" (in en). Scandinavian Journal of Clinical and Laboratory Investigation 82 (6): 461–466. doi:10.1080/00365513.2022.2122076. ISSN 0036-5513. PMID 36129375. https://www.tandfonline.com/doi/full/10.1080/00365513.2022.2122076. 
  19. ↑ Drain, J.; Bishop, J. R.; Hajduk, S. L. (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. https://www.jbc.org/article/S0021-9258(20)89734-8/fulltext. 
  20. ↑ Seed, J. R.; Sechelski, J. B.; Loomis, M. R. (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. https://onlinelibrary.wiley.com/doi/10.1111/j.1550-7408.1990.tb01163.x. 
  21. ↑ Capewell, Paul; Cooper, Anneli; Clucas, Caroline; Weir, William; Macleod, Annette (2015). "A co-evolutionary arms race: trypanosomes shaping the human genome, humans shaping the trypanosome genome". Parasitology 142 Suppl 1 (Suppl 1): S108–119. doi:10.1017/S0031182014000602. ISSN 1469-8161. PMID 25656360. PMC 4413828. https://www.cambridge.org/core/journals/parasitology/article/coevolutionary-arms-race-trypanosomes-shaping-the-human-genome-humans-shaping-the-trypanosome-genome/CDC6284D21BF9D9D5DAE501C80FCFECC. 

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