A unique set of SH3-SH3 interactions controls IB1 homodimerization.
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.
Kristensen
Ole
O
Biostructural Research, Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark. ok@dfuni.dk
Guenat
Sylvie
S
Dar
Imran
I
Allaman-Pillet
Nathalie
N
Abderrahmani
Amar
A
Ferdaoussi
Mourad
M
Roduit
Raphaël
R
Maurer
Fabienne
F
Beckmann
Jacques S
JS
Kastrup
Jette S
JS
Gajhede
Michael
M
Bonny
Christophe
C
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D002460:Cell Line; D018360:Crystallography, X-Ray; D019281:Dimerization; D005786:Gene Expression Regulation / Q000502:physiology*; D051273:Glucose Transporter Type 2 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D017354:Point Mutation; D018909:src Homology Domains / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D051273:Glucose Transporter Type 2; D007328:Insulin; C490666:MAPK8IP1 protein, human; D048670:MAP Kinase Kinase 4