Interdomain interface-mediated target recognition by the Scribble PDZ34 supramodule.
Tandem-arranged PDZ [PSD-95 (postsynaptic density-95), Dlg (discs large homologue) and ZO-1 (zonula occludens-1)] domains often form structural and functional supramodules with distinct target-binding properties. In the present study, we found that the two PDZ domains within the PDZ34 tandem of Scribble, a cell polarity regulator, tightly pack in a 'front-to-back' mode to form a compact supramodule. Although PDZ4 contains a distorted αB/βB pocket, the attachment of PDZ4 to PDZ3 generates an unexpected interdomain pocket that is adjacent to and integrates with the canonical αB/βB pocket of PDZ3 to form an expanded target-binding groove. The structure of the PDZ34-target peptide complex further demonstrated that the peptide binds to this expanded target-binding groove with its upstream residues anchoring into the interdomain pocket directly. Mutations of the interdomain pocket and disruptions of the PDZ34 supramodule both interfere with its target-binding capacity. Therefore, the interdomain interface between the PDZ34 supramodule is intrinsically required for its target recognition and determines its target-binding specificity. This interdomain interface-mediated specific recognition may represent a novel mode of target recognition and would broaden the target-binding versatility for PDZ supramodules. The supramodular nature and target recognition mode of the PDZ34 tandem found in the present study would also help to identify the new binding partners of Scribble and thus may direct further research on the PDZ domain-mediated assembly of Scribble polarity complexes.
*National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Jinqi
J
Ren
*National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Lei
L
Feng
‡State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Yujie
Y
Bai
*National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Haohong
H
Pei
‡State Key Laboratory of Brain and Cognitive Sciences, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Zengqiang
Z
Yuan
*National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
Wei
W
Feng
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D054731:PDZ Domains; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; D011994:Recombinant Proteins; C480591:SCRIB protein, human; D025521:Tumor Suppressor Proteins