1jky

From Proteopedia

(Difference between revisions)

Current revision

Crystal Structure of the Anthrax Lethal Factor (LF): Wild-type LF Complexed with the N-terminal Sequence of MAPKK2

Structural highlights

1jky is a 2 chain structure with sequence from Bacillus anthracis and Homo sapiens. The April 2002 RCSB PDB Molecule of the Month feature on Anthrax Toxin by David S. Goodsell is 10.2210/rcsb_pdb/mom_2002_4. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.9Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LEF_BACAN One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways. Here we describe the crystal structure of LF and its complex with the N terminus of MAPKK-2. LF comprises four domains: domain I binds the membrane-translocating component of anthrax toxin, the protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavage. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recognition. Domain III is inserted into domain II, and seems to have arisen from a repeated duplication of a structural element of domain II. Domain IV is distantly related to the zinc metalloprotease family, and contains the catalytic centre; it also resembles domain I. The structure thus reveals a protein that has evolved through a process of gene duplication, mutation and fusion, into an enzyme with high and unusual specificity.

Crystal structure of the anthrax lethal factor.,Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC Nature. 2001 Nov 8;414(6860):229-33. PMID:11700563^[6]

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

References

↑ Duesbery NS, Webb CP, Leppla SH, Gordon VM, Klimpel KR, Copeland TD, Ahn NG, Oskarsson MK, Fukasawa K, Paull KD, Vande Woude GF. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998 May 1;280(5364):734-7. PMID:9563949
↑ Vitale G, Pellizzari R, Recchi C, Napolitani G, Mock M, Montecucco C. Anthrax lethal factor cleaves the N-terminus of MAPKKs and induces tyrosine/threonine phosphorylation of MAPKs in cultured macrophages. Biochem Biophys Res Commun. 1998 Jul 30;248(3):706-11. PMID:9703991 doi:http://dx.doi.org/S0006-291X(98)99040-4
↑ Duesbery NS, Vande Woude GF. Anthrax lethal factor causes proteolytic inactivation of mitogen-activated protein kinase kinase. J Appl Microbiol. 1999 Aug;87(2):289-93. PMID:10475971
↑ Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000 Dec 15;352 Pt 3:739-45. PMID:11104681
↑ Tang G, Leppla SH. Proteasome activity is required for anthrax lethal toxin to kill macrophages. Infect Immun. 1999 Jun;67(6):3055-60. PMID:10338520
↑ Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC. Crystal structure of the anthrax lethal factor. Nature. 2001 Nov 8;414(6860):229-33. PMID:11700563 doi:10.1038/n35101998

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1jky"

@@ Line 1: / Line 1: @@
-[[Image:1jky.png|left|200px]]
-{{STRUCTURE_1jky|  PDB=1jky  |  SCENE=  }}
+==Crystal Structure of the Anthrax Lethal Factor (LF): Wild-type LF Complexed with the N-terminal Sequence of MAPKK2==
+<StructureSection load='1jky' size='340' side='right'caption='[[1jky]], [[Resolution|resolution]] 3.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[1jky]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The April 2002 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Anthrax Toxin''  by David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2002_4 10.2210/rcsb_pdb/mom_2002_4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JKY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1JKY 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]] 3.9&#8491;</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=1jky FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jky OCA], [https://pdbe.org/1jky PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1jky RCSB], [https://www.ebi.ac.uk/pdbsum/1jky PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1jky ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/LEF_BACAN LEF_BACAN] One of the three proteins composing the anthrax toxin, the agent which infects many mammalian species and that may cause death. LF is the lethal factor that, when associated with PA, causes death. LF is not toxic by itself. It is a protease that cleaves the N-terminal of most dual specificity mitogen-activated protein kinase kinases (MAPKKs or MAP2Ks) (except for MAP2K5). Cleavage invariably occurs within the N-terminal proline-rich region preceding the kinase domain, thus disrupting a sequence involved in directing specific protein-protein interactions necessary for the assembly of signaling complexes. There may be other cytosolic targets of LF involved in cytotoxicity. The proteasome may mediate a toxic process initiated by LF in the cell cytosol involving degradation of unidentified molecules that are essential for macrophage homeostasis. This is an early step in LeTx intoxication, but it is downstream of the cleavage by LF of MEK1 or other putative substrates.<ref>PMID:9563949</ref> <ref>PMID:9703991</ref> <ref>PMID:10475971</ref> <ref>PMID:11104681</ref> <ref>PMID:10338520</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Lethal factor (LF) is a protein (relative molecular mass 90,000) that is critical in the pathogenesis of anthrax. It is a highly specific protease that cleaves members of the mitogen-activated protein kinase kinase (MAPKK) family near to their amino termini, leading to the inhibition of one or more signalling pathways. Here we describe the crystal structure of LF and its complex with the N terminus of MAPKK-2. LF comprises four domains: domain I binds the membrane-translocating component of anthrax toxin, the protective antigen (PA); domains II, III and IV together create a long deep groove that holds the 16-residue N-terminal tail of MAPKK-2 before cleavage. Domain II resembles the ADP-ribosylating toxin from Bacillus cereus, but the active site has been mutated and recruited to augment substrate recognition. Domain III is inserted into domain II, and seems to have arisen from a repeated duplication of a structural element of domain II. Domain IV is distantly related to the zinc metalloprotease family, and contains the catalytic centre; it also resembles domain I. The structure thus reveals a protein that has evolved through a process of gene duplication, mutation and fusion, into an enzyme with high and unusual specificity.
-===Crystal Structure of the Anthrax Lethal Factor (LF): Wild-type LF Complexed with the N-terminal Sequence of MAPKK2===
+Crystal structure of the anthrax lethal factor.,Pannifer AD, Wong TY, Schwarzenbacher R, Renatus M, Petosa C, Bienkowska J, Lacy DB, Collier RJ, Park S, Leppla SH, Hanna P, Liddington RC Nature. 2001 Nov 8;414(6860):229-33. PMID:11700563<ref>PMID:11700563</ref>
-{{ABSTRACT_PUBMED_11700563}}
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-==About this Structure==
+<div class="pdbe-citations 1jky" style="background-color:#fffaf0;"></div>
-[[1jky]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bacillus_anthracis Bacillus anthracis]. The April 2002 RCSB PDB [http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Anthrax Toxin''  by David S. Goodsell is [http://dx.doi.org/10.2210/rcsb_pdb/mom_2002_4 10.2210/rcsb_pdb/mom_2002_4]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1JKY OCA].
 ==See Also==
-*[[Mitogen-activated protein kinase kinase|Mitogen-activated protein kinase kinase]]
+*[[Anthrax lethal factor 3D structures|Anthrax lethal factor 3D structures]]
+== References ==
-==Reference==
+<references/>
-<ref group="xtra">PMID:011700563</ref><references group="xtra"/>
+__TOC__
+</StructureSection>
 [[Category: Anthrax Toxin]]
 [[Category: Bacillus anthracis]]
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
 [[Category: RCSB PDB Molecule of the Month]]
-[[Category: Bienkowska, J.]]
+[[Category: Bienkowska J]]
-[[Category: Collier, R J.]]
+[[Category: Collier RJ]]
-[[Category: Hanna, P.]]
+[[Category: Hanna P]]
-[[Category: Lacy, D B.]]
+[[Category: Lacy DB]]
-[[Category: Leppla, S H.]]
+[[Category: Leppla SH]]
-[[Category: Liddington, R C.]]
+[[Category: Liddington RC]]
-[[Category: Pannifer, A D.]]
+[[Category: Pannifer AD]]
-[[Category: Park, S.]]
+[[Category: Park S]]
-[[Category: Petosa,C.]]
+[[Category: Petosa C]]
-[[Category: Renatus, M.]]
+[[Category: Renatus M]]
-[[Category: Schwarzenbacher, R.]]
+[[Category: Schwarzenbacher R]]
-[[Category: Wong, T Y.]]
+[[Category: Wong TY]]
-[[Category: Lethal toxin]]
-[[Category: Mapkk]]
-[[Category: Mek2]]
-[[Category: Protease-substrate complex]]
-[[Category: Toxin]]
-[[Category: Uncleaved substrate]]

1jky

From Proteopedia

Current revision

Crystal Structure of the Anthrax Lethal Factor (LF): Wild-type LF Complexed with the N-terminal Sequence of MAPKK2

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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