6gje

Structural highlights

Disease

[AMNLS_HUMAN] Graesbeck-Imerslund disease. The disease is caused by mutations affecting the gene represented in this entry. [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.^{[1] [2]}

Function

[AMNLS_HUMAN] Necessary for efficient absorption of vitamin B12 (PubMed:12590260, PubMed:14576052). Required for normal CUBN-mediated protein transport in the kidney. May direct the production of trunk mesoderm during development by modulating a bone morphogenetic protein (BMP) signaling pathway in the underlying visceral endoderm (By similarity).[UniProtKB:Q99JB7]^{[3] [4]} [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.^{[5] [6] [7] [8] [9]}

References

1. ↑ 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
2. ↑ 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
3. ↑ 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
4. ↑ Tanner SM, Aminoff M, Wright FA, Liyanarachchi S, Kuronen M, Saarinen A, Massika O, Mandel H, Broch H, de la Chapelle A. Amnionless, essential for mouse gastrulation, is mutated in recessive hereditary megaloblastic anemia. Nat Genet. 2003 Mar;33(3):426-9. doi: 10.1038/ng1098. Epub 2003 Feb 18. PMID:12590260 doi:http://dx.doi.org/10.1038/ng1098
5. ↑ 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
6. ↑ 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
7. ↑ 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
8. ↑ 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
9. ↑ 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