Six X-linked agammaglobulinemia-causing missense mutations in the src homology 2 domain of Bruton's tyrosine kinase: Phosphotyrosine-binding and circular dichroism analysis
Mattsson, PT ; Lappalainen, I ; Backesjo, CM ; Brockmann, E ; Lauren, S ; Vihinen, Mauno LU
and Smith, CIE
(2000)
In Journal of Immunology
164(8).
p.4170-4177
- Abstract
- Src homology 2 (SH2) domains recognize phosphotyrosine (pY)-containing sequences and thereby mediate their association to ligands. Bruton's tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase, in which mutations cause a hereditary immunodeficiency disease, X-linked agammaglobulinemia (XLA). Mutations have been found in all Btk domains, including SH2, We have analyzed the structural and functional effects of six disease-related amino acid substitutions in the SH2 domain: G302E, R307G, Y334S, L358F, Y361C, and H362Q, Also, we present a novel Btk SH2 missense mutation, H362R, leading to classical XLA, Based on circular dichroism analysis, the conformation of five of the XLA mutants studied differs from the native Btk SH2 domain,... (More)
- Src homology 2 (SH2) domains recognize phosphotyrosine (pY)-containing sequences and thereby mediate their association to ligands. Bruton's tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase, in which mutations cause a hereditary immunodeficiency disease, X-linked agammaglobulinemia (XLA). Mutations have been found in all Btk domains, including SH2, We have analyzed the structural and functional effects of six disease-related amino acid substitutions in the SH2 domain: G302E, R307G, Y334S, L358F, Y361C, and H362Q, Also, we present a novel Btk SH2 missense mutation, H362R, leading to classical XLA, Based on circular dichroism analysis, the conformation of five of the XLA mutants studied differs from the native Btk SH2 domain, while mutant R307G is structurally identical, The binding of XLA mutation-containing SH2 domains to pY-Sepharose was reduced, varying between 1 and 13% of that for the native SH2 domain. The solubility of all the mutated proteins was remarkably reduced. SH2 domain mutations were divided into three categories: 1) Functional mutations, which affect residues presumably participating directly in pY binding (R307G); 2) structural mutations that, via conformational change, not only impair pY binding, but severely derange the structure of the SH2 domain and possibly interfere with the overall conformation of the Btk molecule (G302E, Y334S, L358F, and H362Q); and 3) structural-functional mutations, which contain features from both categories above (Y361C). (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3852172
- author
- Mattsson, PT
; Lappalainen, I
; Backesjo, CM
; Brockmann, E
; Lauren, S
; Vihinen, Mauno
LU
and Smith, CIE
- publishing date
- 2000
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Immunology
- volume
- 164
- issue
- 8
- pages
- 4170 - 4177
- publisher
- American Association of Immunologists
- external identifiers
-
- wos:000086415300032
- scopus:0034655206
- ISSN
- 1550-6606
- language
- English
- LU publication?
- no
- id
- 9d125393-11a6-4b39-aff2-a30b00d9d58f (old id 3852172)
- date added to LUP
- 2016-04-01 16:25:21
- date last changed
- 2022-03-30 07:47:26
@article{9d125393-11a6-4b39-aff2-a30b00d9d58f,
abstract = {{Src homology 2 (SH2) domains recognize phosphotyrosine (pY)-containing sequences and thereby mediate their association to ligands. Bruton's tyrosine kinase (Btk) is a cytoplasmic protein tyrosine kinase, in which mutations cause a hereditary immunodeficiency disease, X-linked agammaglobulinemia (XLA). Mutations have been found in all Btk domains, including SH2, We have analyzed the structural and functional effects of six disease-related amino acid substitutions in the SH2 domain: G302E, R307G, Y334S, L358F, Y361C, and H362Q, Also, we present a novel Btk SH2 missense mutation, H362R, leading to classical XLA, Based on circular dichroism analysis, the conformation of five of the XLA mutants studied differs from the native Btk SH2 domain, while mutant R307G is structurally identical, The binding of XLA mutation-containing SH2 domains to pY-Sepharose was reduced, varying between 1 and 13% of that for the native SH2 domain. The solubility of all the mutated proteins was remarkably reduced. SH2 domain mutations were divided into three categories: 1) Functional mutations, which affect residues presumably participating directly in pY binding (R307G); 2) structural mutations that, via conformational change, not only impair pY binding, but severely derange the structure of the SH2 domain and possibly interfere with the overall conformation of the Btk molecule (G302E, Y334S, L358F, and H362Q); and 3) structural-functional mutations, which contain features from both categories above (Y361C).}},
author = {{Mattsson, PT and Lappalainen, I and Backesjo, CM and Brockmann, E and Lauren, S and Vihinen, Mauno and Smith, CIE}},
issn = {{1550-6606}},
language = {{eng}},
number = {{8}},
pages = {{4170--4177}},
publisher = {{American Association of Immunologists}},
series = {{Journal of Immunology}},
title = {{Six X-linked agammaglobulinemia-causing missense mutations in the src homology 2 domain of Bruton's tyrosine kinase: Phosphotyrosine-binding and circular dichroism analysis}},
volume = {{164}},
year = {{2000}},
}