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| - | [[Image:2bjj.gif|left|200px]]<br /> | |
| - | <applet load="2bjj" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="2bjj, resolution 2.40Å" /> | |
| - | '''STRUCTURE OF RECOMBINANT HUMAN LACTOFERRIN PRODUCED IN THE MILK OF TRANSGENIC COWS'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Structure of recombinant human lactoferrin produced in the milk of transgenic cows== |
| - | Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the, host defence against infection and excessive inflammation. As the, availability of (human milk-derived) natural hLF is limited, alternative, means of production of this biopharmaceutical are extensively researched., Here we report the crystal structure of recombinant hLF (rhLF) expressed, in the milk of transgenic cows at a resolution of 2.4 A. To our knowledge, the first reported structure of a recombinant protein produced in milk of, transgenic livestock. Even though rhLF contains oligomannose- and, hybrid-type N-linked glycans next to complex-type glycans, which are the, only glycans found on natural hLF, the structures are identical within the, experimental error (r.m.s. deviation of only 0.28 A for the main-chain, atoms). Of the differences in polymorphic amino acids between the natural, and rhLF variant used, only the side-chain of Asp561 could be modeled into, the rhLF electron density map. Taken together, the results confirm the, structural integrity of the rhLF variant used in this study. It also, confirms the validity of the transgenic cow mammary gland as a vehicle to, produce recombinant human proteins. | + | <StructureSection load='2bjj' size='340' side='right'caption='[[2bjj]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[2bjj]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2BJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BJJ FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CO3:CARBONATE+ION'>CO3</scene>, <scene name='pdbligand=FE:FE+(III)+ION'>FE</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2bjj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bjj OCA], [https://pdbe.org/2bjj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bjj RCSB], [https://www.ebi.ac.uk/pdbsum/2bjj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bjj ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/TRFL_HUMAN TRFL_HUMAN] Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate.<ref>PMID:12535064</ref> <ref>PMID:22320386</ref> Lactotransferrin has antimicrobial activity which depends on the extracellular cation concentration.<ref>PMID:12535064</ref> <ref>PMID:22320386</ref> Lactoferroxins A, B and C have opioid antagonist activity. Lactoferroxin A shows preference for mu-receptors, while lactoferroxin B and C have somewhat higher degrees of preference for kappa-receptors than for mu-receptors.<ref>PMID:12535064</ref> <ref>PMID:22320386</ref> The lactotransferrin transferrin-like domain 1 functions as a serine protease of the peptidase S60 family that cuts arginine rich regions. This function contributes to the antimicrobial activity.<ref>PMID:12535064</ref> <ref>PMID:22320386</ref> Isoform DeltaLf: transcription factor with antiproliferative properties and inducing cell cycle arrest. Binds to DeltaLf response element found in the SKP1, BAX, DCPS, and SELH promoters.<ref>PMID:12535064</ref> <ref>PMID:22320386</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bj/2bjj_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bjj ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the host defence against infection and excessive inflammation. As the availability of (human milk-derived) natural hLF is limited, alternative means of production of this biopharmaceutical are extensively researched. Here we report the crystal structure of recombinant hLF (rhLF) expressed in the milk of transgenic cows at a resolution of 2.4 A. To our knowledge, the first reported structure of a recombinant protein produced in milk of transgenic livestock. Even though rhLF contains oligomannose- and hybrid-type N-linked glycans next to complex-type glycans, which are the only glycans found on natural hLF, the structures are identical within the experimental error (r.m.s. deviation of only 0.28 A for the main-chain atoms). Of the differences in polymorphic amino acids between the natural and rhLF variant used, only the side-chain of Asp561 could be modeled into the rhLF electron density map. Taken together, the results confirm the structural integrity of the rhLF variant used in this study. It also confirms the validity of the transgenic cow mammary gland as a vehicle to produce recombinant human proteins. |
| | | | |
| - | ==Disease==
| + | The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin.,Thomassen EA, van Veen HA, van Berkel PH, Nuijens JH, Abrahams JP Transgenic Res. 2005 Aug;14(4):397-405. PMID:16201406<ref>PMID:16201406</ref> |
| - | Known disease associated with this structure: Deafness, autosomal dominant 1 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602121 602121]]
| + | |
| | | | |
| - | ==About this Structure==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | 2BJJ is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with NAG, FE and CO3 as [http://en.wikipedia.org/wiki/ligands ligands]. Structure known Active Site: AC1. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BJJ OCA].
| + | </div> |
| | + | <div class="pdbe-citations 2bjj" style="background-color:#fffaf0;"></div> |
| | | | |
| - | ==Reference== | + | ==See Also== |
| - | The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin., Thomassen EA, van Veen HA, van Berkel PH, Nuijens JH, Abrahams JP, Transgenic Res. 2005 Aug;14(4):397-405. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16201406 16201406]
| + | *[[Lactoferrin|Lactoferrin]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Abrahams, J.P.]] | + | [[Category: Abrahams JP]] |
| - | [[Category: Berkel, P.H.C.Van.]]
| + | [[Category: Nuijens JH]] |
| - | [[Category: Nuijens, J.H.]] | + | [[Category: Thomassen EAJ]] |
| - | [[Category: Thomassen, E.A.J.]] | + | [[Category: Van Berkel PHC]] |
| - | [[Category: Veen, H.A.Van.]] | + | [[Category: Van Veen HA]] |
| - | [[Category: CO3]] | + | |
| - | [[Category: FE]]
| + | |
| - | [[Category: NAG]]
| + | |
| - | [[Category: antibiotic]]
| + | |
| - | [[Category: direct protein sequencing]]
| + | |
| - | [[Category: glycoprotein]]
| + | |
| - | [[Category: iron-binding]]
| + | |
| - | [[Category: lactoferrin]]
| + | |
| - | [[Category: metal-binding protein]]
| + | |
| - | [[Category: polymorphism]]
| + | |
| - | [[Category: transgenic cows]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 21:03:21 2007''
| + | |
| Structural highlights
Function
TRFL_HUMAN Transferrins are iron binding transport proteins which can bind two Fe(3+) ions in association with the binding of an anion, usually bicarbonate.[1] [2] Lactotransferrin has antimicrobial activity which depends on the extracellular cation concentration.[3] [4] Lactoferroxins A, B and C have opioid antagonist activity. Lactoferroxin A shows preference for mu-receptors, while lactoferroxin B and C have somewhat higher degrees of preference for kappa-receptors than for mu-receptors.[5] [6] The lactotransferrin transferrin-like domain 1 functions as a serine protease of the peptidase S60 family that cuts arginine rich regions. This function contributes to the antimicrobial activity.[7] [8] Isoform DeltaLf: transcription factor with antiproliferative properties and inducing cell cycle arrest. Binds to DeltaLf response element found in the SKP1, BAX, DCPS, and SELH promoters.[9] [10]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Human lactoferrin (hLF) is an iron-binding glycoprotein involved in the host defence against infection and excessive inflammation. As the availability of (human milk-derived) natural hLF is limited, alternative means of production of this biopharmaceutical are extensively researched. Here we report the crystal structure of recombinant hLF (rhLF) expressed in the milk of transgenic cows at a resolution of 2.4 A. To our knowledge, the first reported structure of a recombinant protein produced in milk of transgenic livestock. Even though rhLF contains oligomannose- and hybrid-type N-linked glycans next to complex-type glycans, which are the only glycans found on natural hLF, the structures are identical within the experimental error (r.m.s. deviation of only 0.28 A for the main-chain atoms). Of the differences in polymorphic amino acids between the natural and rhLF variant used, only the side-chain of Asp561 could be modeled into the rhLF electron density map. Taken together, the results confirm the structural integrity of the rhLF variant used in this study. It also confirms the validity of the transgenic cow mammary gland as a vehicle to produce recombinant human proteins.
The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin.,Thomassen EA, van Veen HA, van Berkel PH, Nuijens JH, Abrahams JP Transgenic Res. 2005 Aug;14(4):397-405. PMID:16201406[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, Plaut AG, St Geme JW 3rd. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003 Feb;47(3):607-17. PMID:12535064
- ↑ Mariller C, Hardiville S, Hoedt E, Huvent I, Pina-Canseco S, Pierce A. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012 Jun;90(3):307-19. doi: 10.1139/o11-070. Epub 2012 Feb 9. PMID:22320386 doi:http://dx.doi.org/10.1139/o11-070
- ↑ Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, Plaut AG, St Geme JW 3rd. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003 Feb;47(3):607-17. PMID:12535064
- ↑ Mariller C, Hardiville S, Hoedt E, Huvent I, Pina-Canseco S, Pierce A. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012 Jun;90(3):307-19. doi: 10.1139/o11-070. Epub 2012 Feb 9. PMID:22320386 doi:http://dx.doi.org/10.1139/o11-070
- ↑ Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, Plaut AG, St Geme JW 3rd. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003 Feb;47(3):607-17. PMID:12535064
- ↑ Mariller C, Hardiville S, Hoedt E, Huvent I, Pina-Canseco S, Pierce A. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012 Jun;90(3):307-19. doi: 10.1139/o11-070. Epub 2012 Feb 9. PMID:22320386 doi:http://dx.doi.org/10.1139/o11-070
- ↑ Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, Plaut AG, St Geme JW 3rd. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003 Feb;47(3):607-17. PMID:12535064
- ↑ Mariller C, Hardiville S, Hoedt E, Huvent I, Pina-Canseco S, Pierce A. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012 Jun;90(3):307-19. doi: 10.1139/o11-070. Epub 2012 Feb 9. PMID:22320386 doi:http://dx.doi.org/10.1139/o11-070
- ↑ Hendrixson DR, Qiu J, Shewry SC, Fink DL, Petty S, Baker EN, Plaut AG, St Geme JW 3rd. Human milk lactoferrin is a serine protease that cleaves Haemophilus surface proteins at arginine-rich sites. Mol Microbiol. 2003 Feb;47(3):607-17. PMID:12535064
- ↑ Mariller C, Hardiville S, Hoedt E, Huvent I, Pina-Canseco S, Pierce A. Delta-lactoferrin, an intracellular lactoferrin isoform that acts as a transcription factor. Biochem Cell Biol. 2012 Jun;90(3):307-19. doi: 10.1139/o11-070. Epub 2012 Feb 9. PMID:22320386 doi:http://dx.doi.org/10.1139/o11-070
- ↑ Thomassen EA, van Veen HA, van Berkel PH, Nuijens JH, Abrahams JP. The protein structure of recombinant human lactoferrin produced in the milk of transgenic cows closely matches the structure of human milk-derived lactoferrin. Transgenic Res. 2005 Aug;14(4):397-405. PMID:16201406
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