| Structural highlights
5f86 is a 2 chain structure with sequence from Drome and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | GOL, SO4 |
| Related: | 5f84, 5f85, 5f87 |
| Gene: | rumi, CG31152 (DROME), F9 (HUMAN) |
| Activity: | Coagulation factor IXa, with EC number 3.4.21.22 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[FA9_HUMAN] Defects in F9 are the cause of recessive X-linked hemophilia B (HEMB) [MIM:306900]; also known as Christmas disease.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] Note=Mutations in position 43 (Oxford-3, San Dimas) and 46 (Cambridge) prevents cleavage of the propeptide, mutation in position 93 (Alabama) probably fails to bind to cell membranes, mutation in position 191 (Chapel-Hill) or in position 226 (Nagoya OR Hilo) prevent cleavage of the activation peptide. Defects in F9 are the cause of thrombophilia due to factor IX defect (THPH8) [MIM:300807]. A hemostatic disorder characterized by a tendency to thrombosis.[37]
Function
[RUMI_DROME] Protein O-glucosyltransferase. Catalyzes the reaction that attaches glucose through an O-glycosidic linkage to a conserved serine residue in epidermal growth factor-like repeats. Regulates Notch signaling by glucosylating Notch in the ER, glucosylation is required for the correct folding and cleavage of Notch.[38] [FA9_HUMAN] Factor IX is a vitamin K-dependent plasma protein that participates in the intrinsic pathway of blood coagulation by converting factor X to its active form in the presence of Ca(2+) ions, phospholipids, and factor VIIIa.
Publication Abstract from PubMed
Rumi O-glucosylates the EGF repeats of a growing list of proteins essential in metazoan development, including Notch. Rumi is essential for Notch signaling, and Rumi dysregulation is linked to several human diseases. Despite Rumi's critical roles, it is unknown how Rumi glucosylates a serine of many but not all EGF repeats. Here we report crystal structures of Drosophila Rumi as binary and ternary complexes with a folded EGF repeat and/or donor substrates. These structures provide insights into the catalytic mechanism and show that Rumi recognizes structural signatures of the EGF motif, the U-shaped consensus sequence, C-X-S-X-(P/A)-C and a conserved hydrophobic region. We found that five Rumi mutations identified in cancers and Dowling-Degos disease are clustered around the enzyme active site and adversely affect its activity. Our study suggests that loss of Rumi activity may underlie these diseases, and the mechanistic insights may facilitate the development of modulators of Notch signaling.
Structural analysis of Notch-regulating Rumi reveals basis for pathogenic mutations.,Yu H, Takeuchi H, Takeuchi M, Liu Q, Kantharia J, Haltiwanger RS, Li H Nat Chem Biol. 2016 Sep;12(9):735-40. doi: 10.1038/nchembio.2135. Epub 2016 Jul, 18. PMID:27428513[39]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ de la Salle C, Charmantier JL, Ravanat C, Ohlmann P, Hartmann ML, Schuhler S, Bischoff R, Ebel C, Roecklin D, Balland A, et al.. The Arg-4 mutant factor IX Strasbourg 2 shows a delayed activation by factor XIa. Nouv Rev Fr Hematol. 1993;35(5):473-80. PMID:8295821
- ↑ Suehiro K, Kawabata S, Miyata T, Takeya H, Takamatsu J, Ogata K, Kamiya T, Saito H, Niho Y, Iwanaga S. Blood clotting factor IX BM Nagoya. Substitution of arginine 180 by tryptophan and its activation by alpha-chymotrypsin and rat mast cell chymase. J Biol Chem. 1989 Dec 15;264(35):21257-65. PMID:2592373
- ↑ Green PM, Bentley DR, Mibashan RS, Nilsson IM, Giannelli F. Molecular pathology of haemophilia B. EMBO J. 1989 Apr;8(4):1067-72. PMID:2743975
- ↑ Noyes CM, Griffith MJ, Roberts HR, Lundblad RL. Identification of the molecular defect in factor IX Chapel Hill: substitution of histidine for arginine at position 145. Proc Natl Acad Sci U S A. 1983 Jul;80(14):4200-2. PMID:6603618
- ↑ Bentley AK, Rees DJ, Rizza C, Brownlee GG. Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4. Cell. 1986 May 9;45(3):343-8. PMID:3009023
- ↑ Davis LM, McGraw RA, Ware JL, Roberts HR, Stafford DW. Factor IXAlabama: a point mutation in a clotting protein results in hemophilia B. Blood. 1987 Jan;69(1):140-3. PMID:3790720
- ↑ Ware J, Davis L, Frazier D, Bajaj SP, Stafford DW. Genetic defect responsible for the dysfunctional protein: factor IXLong Beach. Blood. 1988 Aug;72(2):820-2. PMID:3401602
- ↑ Sugimoto M, Miyata T, Kawabata S, Yoshioka A, Fukui H, Takahashi H, Iwanaga S. Blood clotting factor IX Niigata: substitution of alanine-390 by valine in the catalytic domain. J Biochem. 1988 Dec;104(6):878-80. PMID:3243764
- ↑ Monroe DM, McCord DM, Huang MN, High KA, Lundblad RL, Kasper CK, Roberts HR. Functional consequences of an arginine180 to glutamine mutation in factor IX Hilo. Blood. 1989 May 1;73(6):1540-4. PMID:2713493
- ↑ Attree O, Vidaud D, Vidaud M, Amselem S, Lavergne JM, Goossens M. Mutations in the catalytic domain of human coagulation factor IX: rapid characterization by direct genomic sequencing of DNA fragments displaying an altered melting behavior. Genomics. 1989 Apr;4(3):266-72. PMID:2714791
- ↑ Koeberl DD, Bottema CD, Buerstedde JM, Sommer SS. Functionally important regions of the factor IX gene have a low rate of polymorphism and a high rate of mutation in the dinucleotide CpG. Am J Hum Genet. 1989 Sep;45(3):448-57. PMID:2773937
- ↑ Liddell MB, Peake IR, Taylor SA, Lillicrap DP, Giddings JC, Bloom AL. Factor IX Cardiff: a variant factor IX protein that shows abnormal activation is caused by an arginine to cysteine substitution at position 145. Br J Haematol. 1989 Aug;72(4):556-60. PMID:2775660
- ↑ Sakai T, Yoshioka A, Yamamoto K, Niinomi K, Fujimura Y, Fukui H, Miyata T, Iwanaga S. Blood clotting factor IX Kashihara: amino acid substitution of valine-182 by phenylalanine. J Biochem. 1989 May;105(5):756-9. PMID:2753873
- ↑ Ware J, Diuguid DL, Liebman HA, Rabiet MJ, Kasper CK, Furie BC, Furie B, Stafford DW. Factor IX San Dimas. Substitution of glutamine for Arg-4 in the propeptide leads to incomplete gamma-carboxylation and altered phospholipid binding properties. J Biol Chem. 1989 Jul 5;264(19):11401-6. PMID:2738071
- ↑ Chen SH, Thompson AR, Zhang M, Scott CR. Three point mutations in the factor IX genes of five hemophilia B patients. Identification strategy using localization by altered epitopes in their hemophilic proteins. J Clin Invest. 1989 Jul;84(1):113-8. PMID:2472424 doi:https://dx.doi.org/10.1172/JCI114130
- ↑ Wang NS, Zhang M, Thompson AR, Chen SH. Factor IX Chongqing: a new mutation in the calcium-binding domain of factor IX resulting in severe hemophilia B. Thromb Haemost. 1990 Feb 19;63(1):24-6. PMID:2339358
- ↑ Taylor SA, Liddell MB, Peake IR, Bloom AL, Lillicrap DP. A mutation adjacent to the beta cleavage site of factor IX (valine 182 to leucine) results in mild haemophilia Bm. Br J Haematol. 1990 Jun;75(2):217-21. PMID:2372509
- ↑ Bertina RM, van der Linden IK, Mannucci PM, Reinalda-Poot HH, Cupers R, Poort SR, Reitsma PH. Mutations in hemophilia Bm occur at the Arg180-Val activation site or in the catalytic domain of factor IX. J Biol Chem. 1990 Jul 5;265(19):10876-83. PMID:2162822
- ↑ Miyata T, Sakai T, Sugimoto M, Naka H, Yamamoto K, Yoshioka A, Fukui H, Mitsui K, Kamiya K, Umeyama H, et al.. Factor IX Amagasaki: a new mutation in the catalytic domain resulting in the loss of both coagulant and esterase activities. Biochemistry. 1991 Nov 26;30(47):11286-91. PMID:1958666
- ↑ Sarkar G, Cassady JD, Pyeritz RE, Gilchrist GS, Sommer SS. Isoleucine397 is changed to threonine in two females with hemophilia B. Nucleic Acids Res. 1991 Mar 11;19(5):1165. PMID:1902289
- ↑ Ludwig M, Sabharwal AK, Brackmann HH, Olek K, Smith KJ, Birktoft JJ, Bajaj SP. Hemophilia B caused by five different nondeletion mutations in the protease domain of factor IX. Blood. 1992 Mar 1;79(5):1225-32. PMID:1346975
- ↑ Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP. Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis. Thromb Haemost. 1992 Jan 23;67(1):63-5. PMID:1615485
- ↑ David D, Rosa HA, Pemberton S, Diniz MJ, Campos M, Lavinha J. Single-strand conformation polymorphism (SSCP) analysis of the molecular pathology of hemophilia B. Hum Mutat. 1993;2(5):355-61. PMID:8257988 doi:https://dx.doi.org/10.1002/humu.1380020506
- ↑ Aguilar-Martinez P, Romey MC, Schved JF, Gris JC, Demaille J, Claustres M. Factor IX gene mutations causing haemophilia B: comparison of SSC screening versus systematic DNA sequencing and diagnostic applications. Hum Genet. 1994 Sep;94(3):287-90. PMID:8076946
- ↑ Aguilar-Martinez P, Romey MC, Gris JC, Schved JF, Demaille J, Claustres M. A novel mutation (Val-373 to Glu) in the catalytic domain of factor IX, resulting in moderately/severe hemophilia B in a southern French patient. Hum Mutat. 1994;3(2):156-8. PMID:8199596 doi:https://dx.doi.org/10.1002/humu.1380030211
- ↑ Caglayan SH, Vielhaber E, Gursel T, Aktuglu G, Sommer SS. Identification of mutations in four hemophilia B patients of Turkish origin, including a novel deletion of base 6411. Hum Mutat. 1994;4(2):163-5. PMID:7981722 doi:https://dx.doi.org/10.1002/humu.1380040214
- ↑ Wulff K, Schroder W, Wehnert M, Herrmann FH. Twenty-five novel mutations of the factor IX gene in haemophilia B. Hum Mutat. 1995;6(4):346-8. PMID:8680410 doi:10.1002/humu.1380060410
- ↑ Caglayan SH, Gokmen Y, Aktuglu G, Gurgey A, Sommer SS. Mutations associated with hemophilia B in Turkish patients. Hum Mutat. 1997;10(1):76-9. PMID:9222764 doi:<76::AID-HUMU11>3.0.CO;2-X 10.1002/(SICI)1098-1004(1997)10:1<76::AID-HUMU11>3.0.CO;2-X
- ↑ Chan V, Chan VW, Yip B, Chim CS, Chan TK. Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome. Am J Hematol. 1998 May;58(1):72-6. PMID:9590153
- ↑ David D, Moreira I, Morais S, de Deus G. Five novel factor IX mutations in unrelated hemophilia B patients. Hum Mutat. 1998;Suppl 1:S301-3. PMID:9452115
- ↑ Heit JA, Thorland EC, Ketterling RP, Lind TJ, Daniels TM, Zapata RE, Ordonez SM, Kasper CK, Sommer SS. Germline mutations in Peruvian patients with hemophilia B: pattern of mutation in AmerIndians is similar to the putative endogenous germline pattern. Hum Mutat. 1998;11(5):372-6. PMID:9600455 doi:<372::AID-HUMU4>3.0.CO;2-M 10.1002/(SICI)1098-1004(1998)11:5<372::AID-HUMU4>3.0.CO;2-M
- ↑ Wulff K, Bykowska K, Lopaciuk S, Herrmann FH. Molecular analysis of hemophilia B in Poland: 12 novel mutations of the factor IX gene. Acta Biochim Pol. 1999;46(3):721-6. PMID:10698280
- ↑ Montejo JM, Magallon M, Tizzano E, Solera J. Identification of twenty-one new mutations in the factor IX gene by SSCP analysis. Hum Mutat. 1999;13(2):160-5. PMID:10094553 doi:<160::AID-HUMU9>3.0.CO;2-C 10.1002/(SICI)1098-1004(1999)13:2<160::AID-HUMU9>3.0.CO;2-C
- ↑ Vidal F, Farssac E, Altisent C, Puig L, Gallardo D. Factor IX gene sequencing by a simple and sensitive 15-hour procedure for haemophilia B diagnosis: identification of two novel mutations. Br J Haematol. 2000 Nov;111(2):549-51. PMID:11122099
- ↑ Onay UV, Kavakli K, Kilinc Y, Gurgey A, Aktuglu G, Kemahli S, Ozbek U, Caglayan SH. Molecular pathology of haemophilia B in Turkish patients: identification of a large deletion and 33 independent point mutations. Br J Haematol. 2003 Feb;120(4):656-9. PMID:12588353
- ↑ Espinos C, Casana P, Haya S, Cid AR, Aznar JA. Molecular analyses in hemophilia B families: identification of six new mutations in the factor IX gene. Haematologica. 2003 Feb;88(2):235-6. PMID:12604421
- ↑ Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med. 2009 Oct 22;361(17):1671-5. doi: 10.1056/NEJMoa0904377. PMID:19846852 doi:10.1056/NEJMoa0904377
- ↑ Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell. 2008 Jan 25;132(2):247-58. doi: 10.1016/j.cell.2007.12.016. PMID:18243100 doi:https://dx.doi.org/10.1016/j.cell.2007.12.016
- ↑ Yu H, Takeuchi H, Takeuchi M, Liu Q, Kantharia J, Haltiwanger RS, Li H. Structural analysis of Notch-regulating Rumi reveals basis for pathogenic mutations. Nat Chem Biol. 2016 Sep;12(9):735-40. doi: 10.1038/nchembio.2135. Epub 2016 Jul, 18. PMID:27428513 doi:https://dx.doi.org/10.1038/nchembio.2135
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