4qae

Structural highlights

Disease

[HEPC_HUMAN] Defects in HAMP are the cause of hemochromatosis type 2B (HFE2B) [MIM:613313]; also known as juvenile hemochromatosis (JH). HFE2B is a disorder of iron metabolism with excess deposition of iron in the tissues, bronze skin pigmentation, hepatic cirrhosis, arthropathy and diabetes. The most common symptoms of hemochromatosis type 2 at presentation are hypogonadism and cardiomyopathy.^{[1] [2] [3] [4] [5]}

Function

[HEPC_HUMAN] Seems to act as a signaling molecule involved in the maintenance of iron homeostasis. Seems to be required in conjunction with HFE to regulate both intestinal iron absorption and iron storage in macrophages (By similarity).^[6] Has strong antimicrobial activity against E.coli ML35P N.cinerea and weaker against S.epidermidis, S.aureus and group b streptococcus bacteria. Active against the fungus C.albicans. No activity against P.aeruginosa.^[7] [NGAL_HUMAN] Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Binds iron through association with 2,5-dihydroxybenzoic acid (2,5-DHBA), a siderophore that shares structural similarities with bacterial enterobactin, and delivers or removes iron from the cell, depending on the context. Iron-bound form (holo-24p3) is internalized following binding to the SLC22A17 (24p3R) receptor, leading to release of iron and subsequent increase of intracellular iron concentration. In contrast, association of the iron-free form (apo-24p3) with the SLC22A17 (24p3R) receptor is followed by association with an intracellular siderophore, iron chelation and iron transfer to the extracellular medium, thereby reducing intracellular iron concentration. Involved in apoptosis due to interleukin-3 (IL3) deprivation: iron-loaded form increases intracellular iron concentration without promoting apoptosis, while iron-free form decreases intracellular iron levels, inducing expression of the proapoptotic protein BCL2L11/BIM, resulting in apoptosis. Involved in innate immunity, possibly by sequestrating iron, leading to limit bacterial growth.^[8]

References

1. ↑ Biasiotto G, Belloli S, Ruggeri G, Zanella I, Gerardi G, Corrado M, Gobbi E, Albertini A, Arosio P. Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload. Clin Chem. 2003 Dec;49(12):1981-8. PMID:14633868 doi:10.1373/clinchem.2003.023440
2. ↑ Merryweather-Clarke AT, Cadet E, Bomford A, Capron D, Viprakasit V, Miller A, McHugh PJ, Chapman RW, Pointon JJ, Wimhurst VL, Livesey KJ, Tanphaichitr V, Rochette J, Robson KJ. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis. Hum Mol Genet. 2003 Sep 1;12(17):2241-7. Epub 2003 Jul 15. PMID:12915468 doi:http://dx.doi.org/10.1093/hmg/ddg225
3. ↑ Roetto A, Daraio F, Porporato P, Caruso R, Cox TM, Cazzola M, Gasparini P, Piperno A, Camaschella C. Screening hepcidin for mutations in juvenile hemochromatosis: identification of a new mutation (C70R). Blood. 2004 Mar 15;103(6):2407-9. Epub 2003 Nov 20. PMID:14630809 doi:10.1182/blood-2003-10-3390
4. ↑ Jacolot S, Le Gac G, Scotet V, Quere I, Mura C, Ferec C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood. 2004 Apr 1;103(7):2835-40. Epub 2003 Dec 11. PMID:14670915 doi:10.1182/blood-2003-10-3366
5. ↑ Delatycki MB, Allen KJ, Gow P, MacFarlane J, Radomski C, Thompson J, Hayden MR, Goldberg YP, Samuels ME. A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. Clin Genet. 2004 May;65(5):378-83. PMID:15099344 doi:10.1111/j.0009-9163.2004.00254.x
6. ↑ Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000 Sep 1;480(2-3):147-50. PMID:11034317
7. ↑ Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 2000 Sep 1;480(2-3):147-50. PMID:11034317
8. ↑ Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J. An iron delivery pathway mediated by a lipocalin. Mol Cell. 2002 Nov;10(5):1045-56. PMID:12453413