3kq4

Structural highlights

Disease

[IF_HUMAN] Defects in GIF are the cause of hereditary intrinsic factor deficiency (IFD) [MIM:261000]; also known as congenital pernicious anemia. IFD is an autosomal recessive disorder characterized by megaloblastic anemia.^[1] [CUBN_HUMAN] Grasbeck-Imerslund disease. Defects in CUBN are a cause of recessive hereditary megaloblastic anemia 1 (RH-MGA1) [MIM:261100]; also known as MGA1 Norwegian type or Imerslund-Grasbeck syndrome (I-GS). RH-MGA1 is due to selective malabsorption of vitamin B12. Defects in vitamin B12 absorption lead to impaired function of thymidine synthase. As a consequence DNA synthesis is interrupted. Rapidly dividing cells involved in erythropoiesis are particularly affected.^{[2] [3]}

Function

[IF_HUMAN] Promotes absorption of the essential vitamin cobalamin (Cbl) in the ileum. After interaction with CUBN, the GIF-cobalamin complex is internalized via receptor-mediated endocytosis. [CUBN_HUMAN] Cotransporter which plays a role in lipoprotein, vitamin and iron metabolism, by facilitating their uptake. Binds to ALB, MB, Kappa and lambda-light chains, TF, hemoglobin, GC, SCGB1A1, APOA1, high density lipoprotein, and the GIF-cobalamin complex. The binding of all ligands requires calcium. Serves as important transporter in several absorptive epithelia, including intestine, renal proximal tubules and embryonic yolk sac. Interaction with LRP2 mediates its trafficking throughout vesicles and facilitates the uptake of specific ligands like GC, hemoglobin, ALB, TF and SCGB1A1. Interaction with AMN controls its trafficking to the plasma membrane and facilitates endocytosis of ligands. May play an important role in the development of the peri-implantation embryo through internalization of APOA1 and cholesterol. Binds to LGALS3 at the maternal-fetal interface.^{[4] [5] [6] [7] [8]}

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Tanner SM, Li Z, Perko JD, Oner C, Cetin M, Altay C, Yurtsever Z, David KL, Faivre L, Ismail EA, Grasbeck R, de la Chapelle A. Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene. Proc Natl Acad Sci U S A. 2005 Mar 15;102(11):4130-3. Epub 2005 Feb 28. PMID:15738392 doi:0500517102
2. ↑ Aminoff M, Carter JE, Chadwick RB, Johnson C, Grasbeck R, Abdelaal MA, Broch H, Jenner LB, Verroust PJ, Moestrup SK, de la Chapelle A, Krahe R. Mutations in CUBN, encoding the intrinsic factor-vitamin B12 receptor, cubilin, cause hereditary megaloblastic anaemia 1. Nat Genet. 1999 Mar;21(3):309-13. PMID:10080186 doi:http://dx.doi.org/10.1038/6831
3. ↑ Kristiansen M, Aminoff M, Jacobsen C, de La Chapelle A, Krahe R, Verroust PJ, Moestrup SK. Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. Blood. 2000 Jul 15;96(2):405-9. PMID:10887099
4. ↑ Kozyraki R, Kristiansen M, Silahtaroglu A, Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK. The human intrinsic factor-vitamin B12 receptor, cubilin: molecular characterization and chromosomal mapping of the gene to 10p within the autosomal recessive megaloblastic anemia (MGA1) region. Blood. 1998 May 15;91(10):3593-600. PMID:9572993
5. ↑ Kozyraki R, Fyfe J, Kristiansen M, Gerdes C, Jacobsen C, Cui S, Christensen EI, Aminoff M, de la Chapelle A, Krahe R, Verroust PJ, Moestrup SK. The intrinsic factor-vitamin B12 receptor, cubilin, is a high-affinity apolipoprotein A-I receptor facilitating endocytosis of high-density lipoprotein. Nat Med. 1999 Jun;5(6):656-61. PMID:10371504 doi:http://dx.doi.org/10.1038/9504
6. ↑ Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR, Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13895-900. PMID:11717447 doi:http://dx.doi.org/10.1073/pnas.241516998
7. ↑ Kozyraki R, Fyfe J, Verroust PJ, Jacobsen C, Dautry-Varsat A, Gburek J, Willnow TE, Christensen EI, Moestrup SK. Megalin-dependent cubilin-mediated endocytosis is a major pathway for the apical uptake of transferrin in polarized epithelia. Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12491-6. Epub 2001 Oct 16. PMID:11606717 doi:http://dx.doi.org/10.1073/pnas.211291398
8. ↑ Fyfe JC, Madsen M, Hojrup P, Christensen EI, Tanner SM, de la Chapelle A, He Q, Moestrup SK. The functional cobalamin (vitamin B12)-intrinsic factor receptor is a novel complex of cubilin and amnionless. Blood. 2004 Mar 1;103(5):1573-9. Epub 2003 Oct 23. PMID:14576052 doi:http://dx.doi.org/10.1182/blood-2003-08-2852
9. ↑ Andersen CB, Madsen M, Storm T, Moestrup SK, Andersen GR. Structural basis for receptor recognition of vitamin-B(12)-intrinsic factor complexes. Nature. 2010 Mar 18;464(7287):445-8. PMID:20237569 doi:10.1038/nature08874