1b55
From Proteopedia
(New page: 200px<br /> <applet load="1b55" size="450" color="white" frame="true" align="right" spinBox="true" caption="1b55, resolution 2.4Å" /> '''PH DOMAIN FROM BRUTO...) |
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| - | [[Image:1b55.gif|left|200px]]<br /> | + | [[Image:1b55.gif|left|200px]]<br /><applet load="1b55" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1b55" size=" | + | |
caption="1b55, resolution 2.4Å" /> | caption="1b55, resolution 2.4Å" /> | ||
'''PH DOMAIN FROM BRUTON'S TYROSINE KINASE IN COMPLEX WITH INOSITOL 1,3,4,5-TETRAKISPHOSPHATE'''<br /> | '''PH DOMAIN FROM BRUTON'S TYROSINE KINASE IN COMPLEX WITH INOSITOL 1,3,4,5-TETRAKISPHOSPHATE'''<br /> | ||
==Overview== | ==Overview== | ||
| - | BACKGROUND: The activity of Bruton's tyrosine kinase (Btk) is important | + | BACKGROUND: The activity of Bruton's tyrosine kinase (Btk) is important for the maturation of B cells. A variety of point mutations in this enzyme result in a severe human immunodeficiency known as X-linked agammaglobulinemia (XLA). Btk contains a pleckstrin-homology (PH) domain that specifically binds phosphatidylinositol 3,4,5-trisphosphate and, hence, responds to signalling via phosphatidylinositol 3-kinase. Point mutations in the PH domain might abolish membrane binding, preventing signalling via Btk. RESULTS: We have determined the crystal structures of the wild-type PH domain and a gain-of-function mutant E41K in complex with D-myo-inositol 1,3,4,5-tetra-kisphosphate (Ins (1,3,4,5)P4). The inositol Ins (1,3,4,5)P4 binds to a site that is similar to the inositol 1,4,5-trisphosphate binding site in the PH domain of phospholipase C-delta. A second Ins (1,3,4,5)P4 molecule is associated with the domain of the E41K mutant, suggesting a mechanism for its constitutive interaction with membrane. The affinities of Ins (1,3,4,5)P4 to the wild type (Kd = 40 nM), and several XLA-causing mutants have been measured using isothermal titration calorimetry. CONCLUSIONS: Our data provide an explanation for the specificity and high affinity of the interaction with phosphatidylinositol 3,4,5-trisphosphate and lead to a classification of the XLA mutations that reside in the Btk PH domain. Mis-sense mutations that do not simply destabilize the PH fold either directly affect the interaction with the phosphates of the lipid head group or change electrostatic properties of the lipid-binding site. One point mutation (Q127H) cannot be explained by these facts, suggesting that the PH domain of Btk carries an additional function such as interaction with a Galpha protein. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1B55 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 ZN and 4IP as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http:// | + | 1B55 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 <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=4IP:'>4IP</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1B55 OCA]. |
==Reference== | ==Reference== | ||
| - | Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate., Baraldi E, Carugo | + | Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate., Baraldi E, Djinovic Carugo K, Hyvonen M, Surdo PL, Riley AM, Potter BV, O'Brien R, Ladbury JE, Saraste M, Structure. 1999 Apr 15;7(4):449-60. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10196129 10196129] |
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Transferase]] | [[Category: Transferase]] | ||
[[Category: Baraldi, E.]] | [[Category: Baraldi, E.]] | ||
| - | [[Category: Brien, R | + | [[Category: Brien, R O.]] |
| - | [[Category: Carugo, K | + | [[Category: Carugo, K Djinovic.]] |
[[Category: Hyvoenen, M.]] | [[Category: Hyvoenen, M.]] | ||
| - | [[Category: Ladbury, J | + | [[Category: Ladbury, J E.]] |
| - | [[Category: Potter, B | + | [[Category: Potter, B V.L.]] |
| - | [[Category: Riley, A | + | [[Category: Riley, A M.]] |
[[Category: Saraste, M.]] | [[Category: Saraste, M.]] | ||
| - | [[Category: Surdo, P | + | [[Category: Surdo, P Lo.]] |
[[Category: 4IP]] | [[Category: 4IP]] | ||
[[Category: ZN]] | [[Category: ZN]] | ||
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[[Category: zinc binding]] | [[Category: zinc binding]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:51:36 2008'' |
Revision as of 09:51, 21 February 2008
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PH DOMAIN FROM BRUTON'S TYROSINE KINASE IN COMPLEX WITH INOSITOL 1,3,4,5-TETRAKISPHOSPHATE
Contents |
Overview
BACKGROUND: The activity of Bruton's tyrosine kinase (Btk) is important for the maturation of B cells. A variety of point mutations in this enzyme result in a severe human immunodeficiency known as X-linked agammaglobulinemia (XLA). Btk contains a pleckstrin-homology (PH) domain that specifically binds phosphatidylinositol 3,4,5-trisphosphate and, hence, responds to signalling via phosphatidylinositol 3-kinase. Point mutations in the PH domain might abolish membrane binding, preventing signalling via Btk. RESULTS: We have determined the crystal structures of the wild-type PH domain and a gain-of-function mutant E41K in complex with D-myo-inositol 1,3,4,5-tetra-kisphosphate (Ins (1,3,4,5)P4). The inositol Ins (1,3,4,5)P4 binds to a site that is similar to the inositol 1,4,5-trisphosphate binding site in the PH domain of phospholipase C-delta. A second Ins (1,3,4,5)P4 molecule is associated with the domain of the E41K mutant, suggesting a mechanism for its constitutive interaction with membrane. The affinities of Ins (1,3,4,5)P4 to the wild type (Kd = 40 nM), and several XLA-causing mutants have been measured using isothermal titration calorimetry. CONCLUSIONS: Our data provide an explanation for the specificity and high affinity of the interaction with phosphatidylinositol 3,4,5-trisphosphate and lead to a classification of the XLA mutations that reside in the Btk PH domain. Mis-sense mutations that do not simply destabilize the PH fold either directly affect the interaction with the phosphates of the lipid head group or change electrostatic properties of the lipid-binding site. One point mutation (Q127H) cannot be explained by these facts, suggesting that the PH domain of Btk carries an additional function such as interaction with a Galpha protein.
Disease
Known diseases associated with this structure: Agammaglobulinemia, type 1, X-linked OMIM:[300300], XLA and isolated growth hormone deficiency OMIM:[300300]
About this Structure
1B55 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 Full crystallographic information is available from OCA.
Reference
Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate., Baraldi E, Djinovic Carugo K, Hyvonen M, Surdo PL, Riley AM, Potter BV, O'Brien R, Ladbury JE, Saraste M, Structure. 1999 Apr 15;7(4):449-60. PMID:10196129
Page seeded by OCA on Thu Feb 21 11:51:36 2008
Categories: Homo sapiens | Single protein | Transferase | Baraldi, E. | Brien, R O. | Carugo, K Djinovic. | Hyvoenen, M. | Ladbury, J E. | Potter, B V.L. | Riley, A M. | Saraste, M. | Surdo, P Lo. | 4IP | ZN | 3 | 4 | 5-tetrakisphosphate | Btk motif | Inositol 1 | Ph domain | Tyrosine-protein kinase | X-linked agammaglobulinemia | Zinc binding
