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==structure of FERM protein==
==Structure of FERM protein==
<StructureSection load='7c3m' size='340' side='right'caption='[[7c3m]]' scene=''>
<StructureSection load='7c3m' size='340' side='right'caption='[[7c3m]], [[Resolution|resolution]] 3.60&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C3M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C3M FirstGlance]. <br>
<table><tr><td colspan='2'>[[7c3m]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7C3M OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7C3M FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7c3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c3m OCA], [http://pdbe.org/7c3m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c3m RCSB], [http://www.ebi.ac.uk/pdbsum/7c3m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c3m ProSAT]</span></td></tr>
</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FERMT3, KIND3, MIG2B, URP2 ([http://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'>[http://proteopedia.org/fgij/fg.htm?mol=7c3m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7c3m OCA], [http://pdbe.org/7c3m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7c3m RCSB], [http://www.ebi.ac.uk/pdbsum/7c3m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7c3m ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/URP2_HUMAN URP2_HUMAN]] Leukocyte adhesion deficiency type III. The disease is caused by mutations affecting the gene represented in this entry.<ref>PMID:19064721</ref> <ref>PMID:19234463</ref> <ref>PMID:19234460</ref> <ref>PMID:18779414</ref> <ref>PMID:19617577</ref> 
== Function ==
[[http://www.uniprot.org/uniprot/URP2_HUMAN URP2_HUMAN]] Plays a central role in cell adhesion in hematopoietic cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (By similarity).<ref>PMID:18280249</ref> <ref>PMID:19064721</ref> <ref>PMID:19234463</ref> <ref>PMID:19234460</ref>  Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.<ref>PMID:18280249</ref> <ref>PMID:19064721</ref> <ref>PMID:19234463</ref> <ref>PMID:19234460</ref> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Kindlin-1, -2, and -3 directly bind integrin beta cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin beta cytoplasmic tail as the integrin-binding pocket in the F3 subdomain of 1 protomer is occluded by the pleckstrin homology (PH) domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.
Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state.,Bu W, Levitskaya Z, Loh ZY, Jin S, Basu S, Ero R, Yan X, Wang M, Ngan SFC, Sze SK, Tan SM, Gao YG PLoS Biol. 2020 Jul 9;18(7):e3000755. doi: 10.1371/journal.pbio.3000755., eCollection 2020 Jul. PMID:32644996<ref>PMID:32644996</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7c3m" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Bu, W, Loh, ZY, Jin, S, Basu, S, Ero, R, Park, JE, Yan, X, Wang, M, Sze, SK, Tan, SM, Gao, YG]]
[[Category: Basu, S]]
[[Category: Bu, W]]
[[Category: Ero, R]]
[[Category: Gao, Y G]]
[[Category: Jin, S]]
[[Category: Loh, Z Y]]
[[Category: Park, J E]]
[[Category: Sze, S K]]
[[Category: Tan, S M]]
[[Category: Wang, M]]
[[Category: Yan, X]]
[[Category: Ferm protein]]
[[Category: Integrin]]
[[Category: Kindlin]]
[[Category: Signaling protein]]

Revision as of 14:50, 22 July 2020

Structure of FERM proteinStructure of FERM protein

Structural highlights

7c3m is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
NonStd Res:
Gene:FERMT3, KIND3, MIG2B, URP2 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[URP2_HUMAN] Leukocyte adhesion deficiency type III. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5]

Function

[URP2_HUMAN] Plays a central role in cell adhesion in hematopoietic cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs) (By similarity).[6] [7] [8] [9] Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.[10] [11] [12] [13]

Publication Abstract from PubMed

Kindlin-1, -2, and -3 directly bind integrin beta cytoplasmic tails to regulate integrin activation and signaling. Despite their functional significance and links to several diseases, structural information on full-length kindlin proteins remains unknown. Here, we report the crystal structure of human full-length kindlin-3, which reveals a novel homotrimer state. Unlike kindlin-3 monomer, which is the major population in insect and mammalian cell expression systems, kindlin-3 trimer does not bind integrin beta cytoplasmic tail as the integrin-binding pocket in the F3 subdomain of 1 protomer is occluded by the pleckstrin homology (PH) domain of another protomer, suggesting that kindlin-3 is auto-inhibited upon trimer formation. This is also supported by functional assays in which kindlin-3 knockout K562 erythroleukemia cells reconstituted with the mutant kindlin-3 containing trimer-disrupting mutations exhibited an increase in integrin-mediated adhesion and spreading on fibronectin compared with those reconstituted with wild-type kindlin-3. Taken together, our findings reveal a novel mechanism of kindlin auto-inhibition that involves its homotrimer formation.

Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state.,Bu W, Levitskaya Z, Loh ZY, Jin S, Basu S, Ero R, Yan X, Wang M, Ngan SFC, Sze SK, Tan SM, Gao YG PLoS Biol. 2020 Jul 9;18(7):e3000755. doi: 10.1371/journal.pbio.3000755., eCollection 2020 Jul. PMID:32644996[14]

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

References

  1. ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:http://dx.doi.org/10.1182/blood-2008-10-182154
  2. ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:http://dx.doi.org/10.1038/nm.1931
  3. ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:http://dx.doi.org/10.1038/nm.1917
  4. ↑ Mory A, Feigelson SW, Yarali N, Kilic SS, Bayhan GI, Gershoni-Baruch R, Etzioni A, Alon R. Kindlin-3: a new gene involved in the pathogenesis of LAD-III. Blood. 2008 Sep 15;112(6):2591. doi: 10.1182/blood-2008-06-163162. PMID:18779414 doi:http://dx.doi.org/10.1182/blood-2008-06-163162
  5. ↑ Manevich-Mendelson E, Feigelson SW, Pasvolsky R, Aker M, Grabovsky V, Shulman Z, Kilic SS, Rosenthal-Allieri MA, Ben-Dor S, Mory A, Bernard A, Moser M, Etzioni A, Alon R. Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions. Blood. 2009 Sep 10;114(11):2344-53. doi: 10.1182/blood-2009-04-218636. Epub 2009 , Jul 17. PMID:19617577 doi:http://dx.doi.org/10.1182/blood-2009-04-218636
  6. ↑ Wang L, Deng W, Shi T, Ma D. URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB and apoptosis. Biochem Biophys Res Commun. 2008 Apr 18;368(4):899-906. doi:, 10.1016/j.bbrc.2008.02.024. Epub 2008 Feb 14. PMID:18280249 doi:http://dx.doi.org/10.1016/j.bbrc.2008.02.024
  7. ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:http://dx.doi.org/10.1182/blood-2008-10-182154
  8. ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:http://dx.doi.org/10.1038/nm.1931
  9. ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:http://dx.doi.org/10.1038/nm.1917
  10. ↑ Wang L, Deng W, Shi T, Ma D. URP2SF, a FERM and PH domain containing protein, regulates NF-kappaB and apoptosis. Biochem Biophys Res Commun. 2008 Apr 18;368(4):899-906. doi:, 10.1016/j.bbrc.2008.02.024. Epub 2008 Feb 14. PMID:18280249 doi:http://dx.doi.org/10.1016/j.bbrc.2008.02.024
  11. ↑ Kuijpers TW, van de Vijver E, Weterman MA, de Boer M, Tool AT, van den Berg TK, Moser M, Jakobs ME, Seeger K, Sanal O, Unal S, Cetin M, Roos D, Verhoeven AJ, Baas F. LAD-1/variant syndrome is caused by mutations in FERMT3. Blood. 2009 May 7;113(19):4740-6. doi: 10.1182/blood-2008-10-182154. Epub 2008, Dec 8. PMID:19064721 doi:http://dx.doi.org/10.1182/blood-2008-10-182154
  12. ↑ Svensson L, Howarth K, McDowall A, Patzak I, Evans R, Ussar S, Moser M, Metin A, Fried M, Tomlinson I, Hogg N. Leukocyte adhesion deficiency-III is caused by mutations in KINDLIN3 affecting integrin activation. Nat Med. 2009 Mar;15(3):306-12. doi: 10.1038/nm.1931. Epub 2009 Feb 22. PMID:19234463 doi:http://dx.doi.org/10.1038/nm.1931
  13. ↑ Malinin NL, Zhang L, Choi J, Ciocea A, Razorenova O, Ma YQ, Podrez EA, Tosi M, Lennon DP, Caplan AI, Shurin SB, Plow EF, Byzova TV. A point mutation in KINDLIN3 ablates activation of three integrin subfamilies in humans. Nat Med. 2009 Mar;15(3):313-8. doi: 10.1038/nm.1917. Epub 2009 Feb 22. PMID:19234460 doi:http://dx.doi.org/10.1038/nm.1917
  14. ↑ Bu W, Levitskaya Z, Loh ZY, Jin S, Basu S, Ero R, Yan X, Wang M, Ngan SFC, Sze SK, Tan SM, Gao YG. Structural basis of human full-length kindlin-3 homotrimer in an auto-inhibited state. PLoS Biol. 2020 Jul 9;18(7):e3000755. doi: 10.1371/journal.pbio.3000755., eCollection 2020 Jul. PMID:32644996 doi:http://dx.doi.org/10.1371/journal.pbio.3000755

7c3m, resolution 3.60Å

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