Biochemical studies and molecular dynamics simulations of Smad3-Erbin interaction identify a non-classical Erbin PDZ binding.
In this work, we describe how the Erbin PDZ domain interacts with Smad3, a transductor of the Transforming Growth Factor-beta (TGFbeta) pathway, via its MH2 domain. This interaction was described as important for TGFbeta signaling as it could potentially repress the transcriptional activity of the growth factor. In order to clarify our preliminary experimental observations pointing this interaction, we built a 3D model of the Erbin PDZ/Smad3 MH2 complex and checked its stability using molecular dynamics simulations. This model pointed out charged residues in Smad3 and Erbin which could be important for the interaction. By introducing point mutations of these residues within the proposed binding domains, we experimentally confirmed that arginine 279, glutamic acid 246 in Smad3 and glutamic acid 1321 in Erbin are important for the binding. These data suggest a possible novel interface of binding in the Erbin PDZ domain and reveal an unconventional mode of interaction for a PDZ domain and its ligand.
Déliot
Nadine
N
Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Pharmacologie Moléculaire, F-13009 Marseille, France.
Chavent
Matthieu
M
Nourry
Claire
C
Lécine
Patrick
P
Arnaud
Camille
C
Hermant
Aurélie
A
Maigret
Bernard
B
Borg
Jean-Paul
JP
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054731:PDZ Domains; D011485:Protein Binding; D025941:Protein Interaction Mapping; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C413364:ERBIN protein, human; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D018698:Glutamic Acid; D001120:Arginine