2lri

From Proteopedia

(Difference between revisions)

Revision as of 11:14, 15 February 2023

NMR structure of the second PHD finger of AIRE (AIRE-PHD2)

Structural highlights

2lri is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

AIRE_HUMAN Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:240300. An autosomal recessive disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15] ^[16] ^[17] ^[18] Note=Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes.

Function

AIRE_HUMAN Transcriptional regulator that binds to DNA as a dimer or as a tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Functions as a transcriptional activator and promotes the expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance and the avoidance of autoimmune reactions.^[19]

Publication Abstract from PubMed

Mutations in autoimmune regulator (AIRE) gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of peripheral-tissue antigens to mediate deletional tolerance, thereby preventing self-reactivity. AIRE contains two plant homeodomains (PHDs) which are sites of pathological mutations. AIRE-PHD fingers are important for AIRE transcriptional activity and presumably play a crucial role in the formation of multimeric protein complexes at chromatin level which ultimately control immunological tolerance. As a step forward the understanding of AIRE-PHD fingers in normal and pathological conditions, we investigated their structure and used a proteomic SILAC approach to assess the impact of patient mutations targeting AIRE-PHD fingers. Importantly, both AIRE-PHD fingers are structurally independent and mutually non-interacting domains. In contrast to D297A and V301M on AIRE-PHD1, the C446G mutation on AIRE-PHD2 destroys the structural fold, thus causing aberrant AIRE localization and reduction of AIRE target genes activation. Moreover, mutations targeting AIRE-PHD1 affect the formation of a multimeric protein complex at chromatin level. Overall our results reveal the importance of AIRE-PHD domains in the interaction with chromatin-associated nuclear partners and gene regulation confirming the role of PHD fingers as versatile protein interaction hubs for multiple binding events.

AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome.,Gaetani M, Matafora V, Saare M, Spiliotopoulos D, Mollica L, Quilici G, Chignola F, Mannella V, Zucchelli C, Peterson P, Bachi A, Musco G Nucleic Acids Res. 2012 Dec 1;40(22):11756-68. doi: 10.1093/nar/gks933. Epub 2012, Oct 15. PMID:23074189^[20]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008 Apr;9(4):370-6. doi: 10.1038/sj.embor.2008.11. Epub 2008 Feb 22. PMID:18292755 doi:10.1038/sj.embor.2008.11
↑ Bjorses P, Halonen M, Palvimo JJ, Kolmer M, Aaltonen J, Ellonen P, Perheentupa J, Ulmanen I, Peltonen L. Mutations in the AIRE gene: effects on subcellular location and transactivation function of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy protein. Am J Hum Genet. 2000 Feb;66(2):378-92. PMID:10677297 doi:10.1086/302765
↑ Pitkanen J, Vahamurto P, Krohn K, Peterson P. Subcellular localization of the autoimmune regulator protein. characterization of nuclear targeting and transcriptional activation domain. J Biol Chem. 2001 Jun 1;276(22):19597-602. Epub 2001 Mar 26. PMID:11274163 doi:10.1074/jbc.M008322200
↑ Halonen M, Kangas H, Ruppell T, Ilmarinen T, Ollila J, Kolmer M, Vihinen M, Palvimo J, Saarela J, Ulmanen I, Eskelin P. APECED-causing mutations in AIRE reveal the functional domains of the protein. Hum Mutat. 2004 Mar;23(3):245-57. PMID:14974083 doi:10.1002/humu.20003
↑ Nagamine K, Peterson P, Scott HS, Kudoh J, Minoshima S, Heino M, Krohn KJ, Lalioti MD, Mullis PE, Antonarakis SE, Kawasaki K, Asakawa S, Ito F, Shimizu N. Positional cloning of the APECED gene. Nat Genet. 1997 Dec;17(4):393-8. PMID:9398839 doi:10.1038/ng1297-393
↑ Bottomley MJ, Stier G, Pennacchini D, Legube G, Simon B, Akhtar A, Sattler M, Musco G. NMR structure of the first PHD finger of autoimmune regulator protein (AIRE1). Insights into autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) disease. J Biol Chem. 2005 Mar 25;280(12):11505-12. Epub 2005 Jan 13. PMID:15649886 doi:http://dx.doi.org/10.1074/jbc.M413959200
↑ Chakravarty S, Zeng L, Zhou MM. Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator. Structure. 2009 May 13;17(5):670-9. PMID:19446523 doi:10.1016/j.str.2009.02.017
↑ Heino M, Scott HS, Chen Q, Peterson P, Maebpaa U, Papasavvas MP, Mittaz L, Barras C, Rossier C, Chrousos GP, Stratakis CA, Nagamine K, Kudoh J, Shimizu N, Maclaren N, Antonarakis SE, Krohn K. Mutation analyses of North American APS-1 patients. Hum Mutat. 1999;13(1):69-74. PMID:9888391 doi:<69::AID-HUMU8>3.0.CO;2-6 10.1002/(SICI)1098-1004(1999)13:1<69::AID-HUMU8>3.0.CO;2-6
↑ Saugier-Veber P, Drouot N, Wolf LM, Kuhn JM, Frebourg T, Lefebvre H. Identification of a novel mutation in the autoimmune regulator (AIRE-1) gene in a French family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Eur J Endocrinol. 2001 Apr;144(4):347-51. PMID:11275943
↑ Heino M, Peterson P, Kudoh J, Shimizu N, Antonarakis SE, Scott HS, Krohn K. APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat. 2001 Sep;18(3):205-11. PMID:11524731 doi:10.1002/humu.1176
↑ Cihakova D, Trebusak K, Heino M, Fadeyev V, Tiulpakov A, Battelino T, Tar A, Halasz Z, Blumel P, Tawfik S, Krohn K, Lebl J, Peterson P. Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED. Hum Mutat. 2001 Sep;18(3):225-32. PMID:11524733 doi:10.1002/humu.1178
↑ Cetani F, Barbesino G, Borsari S, Pardi E, Cianferotti L, Pinchera A, Marcocci C. A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis. J Clin Endocrinol Metab. 2001 Oct;86(10):4747-52. PMID:11600535
↑ Kogawa K, Kudoh J, Nagafuchi S, Ohga S, Katsuta H, Ishibashi H, Harada M, Hara T, Shimizu N. Distinct clinical phenotype and immunoreactivity in Japanese siblings with autoimmune polyglandular syndrome type 1 (APS-1) associated with compound heterozygous novel AIRE gene mutations. Clin Immunol. 2002 Jun;103(3 Pt 1):277-83. PMID:12173302
↑ Sato K, Nakajima K, Imamura H, Deguchi T, Horinouchi S, Yamazaki K, Yamada E, Kanaji Y, Takano K. A novel missense mutation of AIRE gene in a patient with autoimmune polyendocrinopathy, candidiasis and ectodermal dystrophy (APECED), accompanied with progressive muscular atrophy: case report and review of the literature in Japan. Endocr J. 2002 Dec;49(6):625-33. PMID:12625412
↑ Meloni A, Perniola R, Faa V, Corvaglia E, Cao A, Rosatelli MC. Delineation of the molecular defects in the AIRE gene in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients from Southern Italy. J Clin Endocrinol Metab. 2002 Feb;87(2):841-6. PMID:11836330
↑ Halonen M, Eskelin P, Myhre AG, Perheentupa J, Husebye ES, Kampe O, Rorsman F, Peltonen L, Ulmanen I, Partanen J. AIRE mutations and human leukocyte antigen genotypes as determinants of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy phenotype. J Clin Endocrinol Metab. 2002 Jun;87(6):2568-74. PMID:12050215
↑ Meloni A, Fiorillo E, Corda D, Perniola R, Cao A, Rosatelli MC. Two novel mutations of the AIRE protein affecting its homodimerization properties. Hum Mutat. 2005 Mar;25(3):319. PMID:15712268 doi:10.1002/humu.9309
↑ Ilmarinen T, Eskelin P, Halonen M, Ruppell T, Kilpikari R, Torres GD, Kangas H, Ulmanen I. Functional analysis of SAND mutations in AIRE supports dominant inheritance of the G228W mutation. Hum Mutat. 2005 Oct;26(4):322-31. PMID:16114041 doi:10.1002/humu.20224
↑ Org T, Chignola F, Hetenyi C, Gaetani M, Rebane A, Liiv I, Maran U, Mollica L, Bottomley MJ, Musco G, Peterson P. The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression. EMBO Rep. 2008 Apr;9(4):370-6. doi: 10.1038/sj.embor.2008.11. Epub 2008 Feb 22. PMID:18292755 doi:10.1038/sj.embor.2008.11
↑ Gaetani M, Matafora V, Saare M, Spiliotopoulos D, Mollica L, Quilici G, Chignola F, Mannella V, Zucchelli C, Peterson P, Bachi A, Musco G. AIRE-PHD fingers are structural hubs to maintain the integrity of chromatin-associated interactome. Nucleic Acids Res. 2012 Dec 1;40(22):11756-68. doi: 10.1093/nar/gks933. Epub 2012, Oct 15. PMID:23074189 doi:http://dx.doi.org/10.1093/nar/gks933

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2lri"

@@ Line 1: / Line 1: @@
 ==NMR structure of the second PHD finger of AIRE (AIRE-PHD2)==
-<StructureSection load='2lri' size='340' side='right'caption='[[2lri]], [[NMR_Ensembles_of_Models | 50 NMR models]]' scene=''>
+<StructureSection load='2lri' size='340' side='right'caption='[[2lri]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2lri]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LRI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LRI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2lri]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2LRI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2LRI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AIRE, APECED ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=2lri FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2lri OCA], [https://pdbe.org/2lri PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2lri RCSB], [https://www.ebi.ac.uk/pdbsum/2lri PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2lri ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN]] Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:[https://omim.org/entry/240300 240300]]. An autosomal recessive disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism.<ref>PMID:18292755</ref> <ref>PMID:10677297</ref> <ref>PMID:11274163</ref> <ref>PMID:14974083</ref> <ref>PMID:9398839</ref> <ref>PMID:15649886</ref> <ref>PMID:19446523</ref> <ref>PMID:9888391</ref> <ref>PMID:11275943</ref> <ref>PMID:11524731</ref> <ref>PMID:11524733</ref> <ref>PMID:11600535</ref> <ref>PMID:12173302</ref> <ref>PMID:12625412</ref> <ref>PMID:11836330</ref> <ref>PMID:12050215</ref> <ref>PMID:15712268</ref> <ref>PMID:16114041</ref>   Note=Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes.
+[https://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN] Defects in AIRE are a cause of autoimmune poly-endocrinopathy candidiasis ectodermal dystrophy (APS1) [MIM:[https://omim.org/entry/240300 240300]. An autosomal recessive disease characterized by the combination of chronic mucocutaneous candidiasis, hypoparathyroidism and Addison disease. Symptoms of mucocutaneous candidiasis manifest first, followed by hypotension or fatigue occurring as a result of Addison disease. APS1 is associated with other autoimmune disorders including diabetes mellitus, vitiligo, alopecia, hepatitis, pernicious anemia and primary hypothyroidism.<ref>PMID:18292755</ref> <ref>PMID:10677297</ref> <ref>PMID:11274163</ref> <ref>PMID:14974083</ref> <ref>PMID:9398839</ref> <ref>PMID:15649886</ref> <ref>PMID:19446523</ref> <ref>PMID:9888391</ref> <ref>PMID:11275943</ref> <ref>PMID:11524731</ref> <ref>PMID:11524733</ref> <ref>PMID:11600535</ref> <ref>PMID:12173302</ref> <ref>PMID:12625412</ref> <ref>PMID:11836330</ref> <ref>PMID:12050215</ref> <ref>PMID:15712268</ref> <ref>PMID:16114041</ref>   Note=Most of the mutations alter the nucleus-cytoplasm distribution of AIRE and disturb its association with nuclear dots and cytoplasmic filaments. Most of the mutations also decrease transactivation of the protein. The HSR domain is responsible for the homomultimerization activity of AIRE. All the missense mutations of the HSR and the SAND domains decrease this activity, but those in other domains do not. The AIRE protein is present in soluble high-molecular-weight complexes. Mutations in the HSR domain and deletion of PHD zinc fingers disturb the formation of these complexes.
 == Function ==
-[[https://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN]] Transcriptional regulator that binds to DNA as a dimer or as a tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Functions as a transcriptional activator and promotes the expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance and the avoidance of autoimmune reactions.<ref>PMID:18292755</ref>
+[https://www.uniprot.org/uniprot/AIRE_HUMAN AIRE_HUMAN] Transcriptional regulator that binds to DNA as a dimer or as a tetramer, but not as a monomer. Binds to G-doublets in an A/T-rich environment; the preferred motif is a tandem repeat of 5'-. ATTGGTTA-3' combined with a 5'-TTATTA-3' box. Binds to nucleosomes (By similarity). Binds to chromatin and interacts selectively with histone H3 that is not methylated at 'Lys-4', not phosphorylated at 'Thr-3' and not methylated at 'Arg-2'. Functions as a sensor of histone H3 modifications that are important for the epigenetic regulation of gene expression. Functions as a transcriptional activator and promotes the expression of otherwise tissue-specific self-antigens in the thymus, which is important for self tolerance and the avoidance of autoimmune reactions.<ref>PMID:18292755</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 25: / Line 24: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Chignola, F]]
+[[Category: Chignola F]]
-[[Category: Gaetani, M]]
+[[Category: Gaetani M]]
-[[Category: Mannella, V]]
+[[Category: Mannella V]]
-[[Category: Mollica, L]]
+[[Category: Mollica L]]
-[[Category: Musco, G]]
+[[Category: Musco G]]
-[[Category: Quilici, G]]
+[[Category: Quilici G]]
-[[Category: Spiliotopoulos, D]]
+[[Category: Spiliotopoulos D]]
-[[Category: Apeced]]
-[[Category: Transcription]]
-[[Category: Zn binding protein domain]]

2lri

From Proteopedia

Revision as of 11:14, 15 February 2023

NMR structure of the second PHD finger of AIRE (AIRE-PHD2)

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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