1hh8: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(20 intermediate revisions by the same user not shown)
Line 1: Line 1:
[[Image:1hh8.gif|left|200px]]<br />
<applet load="1hh8" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1hh8, resolution 1.8&Aring;" />
'''THE ACTIVE N-TERMINAL REGION OF P67PHOX: STRUCTURE AT 1.8 ANGSTROM RESOLUTION AND BIOCHEMICAL CHARACTERIZATIONS OF THE A128V MUTANT IMPLICATED IN CHRONIC GRANULOMATOUS DISEASE'''<br />


==Overview==
==The active N-terminal region of p67phox: Structure at 1.8 Angstrom resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease==
Upon activation, the NADPH oxidase from neutrophils produces superoxide, anions in response to microbial infection. This enzymatic complex is, activated by association of its cytosolic factors p67(phox), p47(phox), and the small G protein Rac with a membrane-associated flavocytochrome, b(558). Here we report the crystal structure of the active N-terminal, fragment of p67(phox) at 1.8 A resolution, as well as functional studies, of p67(phox) mutants. This N-terminal region (residues 1-213) consists, mainly of four TPR (tetratricopeptide repeat) motifs in which the C, terminus folds back into a hydrophobic groove formed by the TPR domain., The structure is very similar to that of the inactive truncated form of, p67(phox) bound to the small G protein Rac previously reported, but, differs by the presence of a short C-terminal helix (residues 187-193), that might be part of the activation domain. All p67(phox) mutants, responsible for Chronic Granulomatous Disease (CGD), a severe defect of, NADPH oxidase function, are localized in the N-terminal region. We, investigated two CGD mutations, G78E and A128V. Surprisingly, the A128V, CGD mutant is able to fully activate the NADPH oxidase in vitro at 25, degrees C. However, this point mutation represents a temperature-sensitive, defect in p67(phox) that explains its phenotype at physiological, temperature.
<StructureSection load='1hh8' size='340' side='right'caption='[[1hh8]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1hh8]] 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=1HH8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1HH8 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]] 1.8&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FLC:CITRATE+ANION'>FLC</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=1hh8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1hh8 OCA], [https://pdbe.org/1hh8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1hh8 RCSB], [https://www.ebi.ac.uk/pdbsum/1hh8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1hh8 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/NCF2_HUMAN NCF2_HUMAN] Defects in NCF2 are a cause of chronic granulomatous disease autosomal recessive cytochrome-b-positive type 2 (CGD2) [MIM:[https://omim.org/entry/233710 233710]. Chronic granulomatous disease is a genetically heterogeneous disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.<ref>PMID:8286749</ref> <ref>PMID:9070911</ref> <ref>PMID:10498624</ref> <ref>PMID:10598813</ref> <ref>PMID:11112388</ref> <ref>PMID:16937026</ref> <ref>PMID:18625437</ref> <ref>PMID:19624736</ref> <ref>PMID:20167518</ref>
== Function ==
[https://www.uniprot.org/uniprot/NCF2_HUMAN NCF2_HUMAN] NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).
== 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/hh/1hh8_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=1hh8 ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Upon activation, the NADPH oxidase from neutrophils produces superoxide anions in response to microbial infection. This enzymatic complex is activated by association of its cytosolic factors p67(phox), p47(phox), and the small G protein Rac with a membrane-associated flavocytochrome b(558). Here we report the crystal structure of the active N-terminal fragment of p67(phox) at 1.8 A resolution, as well as functional studies of p67(phox) mutants. This N-terminal region (residues 1-213) consists mainly of four TPR (tetratricopeptide repeat) motifs in which the C terminus folds back into a hydrophobic groove formed by the TPR domain. The structure is very similar to that of the inactive truncated form of p67(phox) bound to the small G protein Rac previously reported, but differs by the presence of a short C-terminal helix (residues 187-193) that might be part of the activation domain. All p67(phox) mutants responsible for Chronic Granulomatous Disease (CGD), a severe defect of NADPH oxidase function, are localized in the N-terminal region. We investigated two CGD mutations, G78E and A128V. Surprisingly, the A128V CGD mutant is able to fully activate the NADPH oxidase in vitro at 25 degrees C. However, this point mutation represents a temperature-sensitive defect in p67(phox) that explains its phenotype at physiological temperature.


==About this Structure==
The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease.,Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E J Biol Chem. 2001 Jun 15;276(24):21627-31. Epub 2001 Mar 21. PMID:11262407<ref>PMID:11262407</ref>
1HH8 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 FLC as [http://en.wikipedia.org/wiki/ligand ligand]. Structure known Active Site: FLC. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1HH8 OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease., Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E, J Biol Chem. 2001 Jun 15;276(24):21627-31. Epub 2001 Mar 21. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11262407 11262407]
</div>
<div class="pdbe-citations 1hh8" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[NADPH oxidase 3D structures|NADPH oxidase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Dagher, M.C.]]
[[Category: Dagher M-C]]
[[Category: Fieschi, F.]]
[[Category: Fieschi F]]
[[Category: Grizot, S.]]
[[Category: Grizot S]]
[[Category: Pebay-Peyroula, E.]]
[[Category: Pebay-Peyroula E]]
[[Category: FLC]]
[[Category: phagocyte oxidase factor]]
[[Category: repeat]]
[[Category: sh3 domain]]
[[Category: tpr repeat]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov  5 13:40:32 2007''

Latest revision as of 11:56, 9 May 2024

The active N-terminal region of p67phox: Structure at 1.8 Angstrom resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous diseaseThe active N-terminal region of p67phox: Structure at 1.8 Angstrom resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease

Structural highlights

1hh8 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NCF2_HUMAN Defects in NCF2 are a cause of chronic granulomatous disease autosomal recessive cytochrome-b-positive type 2 (CGD2) [MIM:233710. Chronic granulomatous disease is a genetically heterogeneous disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.[1] [2] [3] [4] [5] [6] [7] [8] [9]

Function

NCF2_HUMAN NCF2, NCF1, and a membrane bound cytochrome b558 are required for activation of the latent NADPH oxidase (necessary for superoxide production).

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

Upon activation, the NADPH oxidase from neutrophils produces superoxide anions in response to microbial infection. This enzymatic complex is activated by association of its cytosolic factors p67(phox), p47(phox), and the small G protein Rac with a membrane-associated flavocytochrome b(558). Here we report the crystal structure of the active N-terminal fragment of p67(phox) at 1.8 A resolution, as well as functional studies of p67(phox) mutants. This N-terminal region (residues 1-213) consists mainly of four TPR (tetratricopeptide repeat) motifs in which the C terminus folds back into a hydrophobic groove formed by the TPR domain. The structure is very similar to that of the inactive truncated form of p67(phox) bound to the small G protein Rac previously reported, but differs by the presence of a short C-terminal helix (residues 187-193) that might be part of the activation domain. All p67(phox) mutants responsible for Chronic Granulomatous Disease (CGD), a severe defect of NADPH oxidase function, are localized in the N-terminal region. We investigated two CGD mutations, G78E and A128V. Surprisingly, the A128V CGD mutant is able to fully activate the NADPH oxidase in vitro at 25 degrees C. However, this point mutation represents a temperature-sensitive defect in p67(phox) that explains its phenotype at physiological temperature.

The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease.,Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E J Biol Chem. 2001 Jun 15;276(24):21627-31. Epub 2001 Mar 21. PMID:11262407[10]

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

See Also

References

  1. ↑ de Boer M, Hilarius-Stokman PM, Hossle JP, Verhoeven AJ, Graf N, Kenney RT, Seger R, Roos D. Autosomal recessive chronic granulomatous disease with absence of the 67-kD cytosolic NADPH oxidase component: identification of mutation and detection of carriers. Blood. 1994 Jan 15;83(2):531-6. PMID:8286749
  2. ↑ Bonizzato A, Russo MP, Donini M, Dusi S. Identification of a double mutation (D160V-K161E) in the p67phox gene of a chronic granulomatous disease patient. Biochem Biophys Res Commun. 1997 Feb 24;231(3):861-3. PMID:9070911 doi:S0006-291X(97)96204-5
  3. ↑ Patino PJ, Rae J, Noack D, Erickson R, Ding J, de Olarte DG, Curnutte JT. Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox. Blood. 1999 Oct 1;94(7):2505-14. PMID:10498624
  4. ↑ Noack D, Rae J, Cross AR, Munoz J, Salmen S, Mendoza JA, Rossi N, Curnutte JT, Heyworth PG. Autosomal recessive chronic granulomatous disease caused by novel mutations in NCF-2, the gene encoding the p67-phox component of phagocyte NADPH oxidase. Hum Genet. 1999 Nov;105(5):460-7. PMID:10598813
  5. ↑ Cross AR, Noack D, Rae J, Curnutte JT, Heyworth PG. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update). Blood Cells Mol Dis. 2000 Oct;26(5):561-5. PMID:11112388 doi:10.1006/bcmd.2000.0333
  6. ↑ El Kares R, Barbouche MR, Elloumi-Zghal H, Bejaoui M, Chemli J, Mellouli F, Tebib N, Abdelmoula MS, Boukthir S, Fitouri Z, M'Rad S, Bouslama K, Touiri H, Abdelhak S, Dellagi MK. Genetic and mutational heterogeneity of autosomal recessive chronic granulomatous disease in Tunisia. J Hum Genet. 2006;51(10):887-95. Epub 2006 Aug 26. PMID:16937026 doi:10.1007/s10038-006-0039-8
  7. ↑ Yu G, Hong DK, Dionis KY, Rae J, Heyworth PG, Curnutte JT, Lewis DB. Focus on FOCIS: the continuing diagnostic challenge of autosomal recessive chronic granulomatous disease. Clin Immunol. 2008 Aug;128(2):117-26. doi: 10.1016/j.clim.2008.05.008. PMID:18625437 doi:10.1016/j.clim.2008.05.008
  8. ↑ Koker MY, Sanal O, van Leeuwen K, de Boer M, Metin A, Patiroglu T, Ozgur TT, Tezcan I, Roos D. Four different NCF2 mutations in six families from Turkey and an overview of NCF2 gene mutations. Eur J Clin Invest. 2009 Oct;39(10):942-51. doi: 10.1111/j.1365-2362.2009.02195.x., Epub 2009 Jul 17. PMID:19624736 doi:10.1111/j.1365-2362.2009.02195.x
  9. ↑ Roos D, Kuhns DB, Maddalena A, Bustamante J, Kannengiesser C, de Boer M, van Leeuwen K, Koker MY, Wolach B, Roesler J, Malech HL, Holland SM, Gallin JI, Stasia MJ. Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (second update). Blood Cells Mol Dis. 2010 Apr 15;44(4):291-9. doi: 10.1016/j.bcmd.2010.01.009., Epub 2010 Feb 18. PMID:20167518 doi:10.1016/j.bcmd.2010.01.009
  10. ↑ Grizot S, Fieschi F, Dagher MC, Pebay-Peyroula E. The active N-terminal region of p67phox. Structure at 1.8 A resolution and biochemical characterizations of the A128V mutant implicated in chronic granulomatous disease. J Biol Chem. 2001 Jun 15;276(24):21627-31. Epub 2001 Mar 21. PMID:11262407 doi:http://dx.doi.org/10.1074/jbc.M100893200

1hh8, resolution 1.80Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=1hh8&oldid=4143553"