A unique set of SH3-SH3 interactions controls IB1 homodimerization
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A unique set of SH3-SH3 interactions controls IB1 homodimerization. / Kristensen, Ole; Guenat, Sylvie; Dar, Imran; Allaman-Pillet, Nathalie; Abderrahmani, Amar; Ferdaoussi, Mourad; Roduit, Raphaël; Maurer, Fabienne; Beckmann, Jacques S; Kastrup, Jette S; Gajhede, Michael; Bonny, Christophe.
In: E M B O Journal, Vol. 25, No. 4, 2006, p. 785-97.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A unique set of SH3-SH3 interactions controls IB1 homodimerization
AU - Kristensen, Ole
AU - Guenat, Sylvie
AU - Dar, Imran
AU - Allaman-Pillet, Nathalie
AU - Abderrahmani, Amar
AU - Ferdaoussi, Mourad
AU - Roduit, Raphaël
AU - Maurer, Fabienne
AU - Beckmann, Jacques S
AU - Kastrup, Jette S
AU - Gajhede, Michael
AU - Bonny, Christophe
PY - 2006
Y1 - 2006
N2 - Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components and secretion. IB1 has been shown to homodimerize, but neither the molecular mechanisms nor the function of dimerization have yet been characterized. Here, we show that IB1 homodimerizes through a novel and unique set of Src homology 3 (SH3)-SH3 interactions. X-ray crystallography studies show that the dimer interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB1 SH3 domain lacks this motif. The highly stable IB1 homodimer can be significantly destabilized in vitro by three individual point mutations directed against key residues involved in dimerization. Each mutation reduces IB1-dependent basal JNK activity in 293T cells. Impaired dimerization also results in a reduction in glucose transporter type 2 expression and in glucose-dependent insulin secretion in pancreatic beta-cells. Taken together, these results indicate that IB1 homodimerization through its SH3 domain has pleiotropic effects including regulation of the insulin secretion process.
AB - Islet-brain 1 (IB1 or JIP-1) is a scaffold protein that interacts with components of the c-Jun N-terminal kinase (JNK) signal-transduction pathway. IB1 is expressed at high levels in neurons and in pancreatic beta-cells, where it controls expression of several insulin-secretory components and secretion. IB1 has been shown to homodimerize, but neither the molecular mechanisms nor the function of dimerization have yet been characterized. Here, we show that IB1 homodimerizes through a novel and unique set of Src homology 3 (SH3)-SH3 interactions. X-ray crystallography studies show that the dimer interface covers a region usually engaged in PxxP-mediated ligand recognition, even though the IB1 SH3 domain lacks this motif. The highly stable IB1 homodimer can be significantly destabilized in vitro by three individual point mutations directed against key residues involved in dimerization. Each mutation reduces IB1-dependent basal JNK activity in 293T cells. Impaired dimerization also results in a reduction in glucose transporter type 2 expression and in glucose-dependent insulin secretion in pancreatic beta-cells. Taken together, these results indicate that IB1 homodimerization through its SH3 domain has pleiotropic effects including regulation of the insulin secretion process.
KW - Adaptor Proteins, Signal Transducing
KW - Amino Acid Substitution
KW - Cell Line
KW - Crystallography, X-Ray
KW - Dimerization
KW - Gene Expression Regulation
KW - Glucose Transporter Type 2
KW - Humans
KW - Insulin
KW - Insulin-Secreting Cells
KW - MAP Kinase Kinase 4
KW - Neurons
KW - Point Mutation
KW - src Homology Domains
U2 - 10.1038/sj.emboj.7600982
DO - 10.1038/sj.emboj.7600982
M3 - Journal article
C2 - 16456539
VL - 25
SP - 785
EP - 797
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 4
ER -
ID: 40318018