期刊
CURRENT RESEARCH IN STRUCTURAL BIOLOGY
卷 3, 期 -, 页码 41-50出版社
ELSEVIER
DOI: 10.1016/j.crstbi.2021.01.001
关键词
PDZ domain; Phage display; Short linear motif; SLiM; PDZbm; Shank; ARAP3
资金
- Swedish research council [2016-04965]
- European Union's Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie Grant [675341]
- German Research Foundation (DFG) [JO 1473/1-3]
- AbbVie
- Bayer AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genentech
- Genome Canada through Ontario Genomics Institute [OGI-196]
- EU/EFPIA/OICR/McGill/KTH/Diamond
- Innovative Medicines Initiative 2 Joint Undertaking [EUbOPEN] [875510]
- Janssen
- Merck KGaA
- Merck Co
- Pfizer
- Sao Paulo Research Foundation-FAPESP
- Takeda
- Wellcome [106169/ZZ14/Z]
- European Union's Horizon 2020 research and innovation program [730872]
- Knut and Alice Wallenberg Foundation
PDZ domains are a large family of modular domains known for binding C-terminal motifs of target proteins, but the interaction involving internal PDZ binding motifs (PDZbms) remains poorly studied. Using the PDZ domain of Shank1 as a model, this study explored internal PDZbm-mediated interactions, expanding the interactome of Shank1 and indicating a largely unexplored interaction space of PDZ domains. The findings revealed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins, and the affinities of PDZbm interactions are in the low micromolar range.
PDZ domains constitute a large family of modular domains that are well-known for binding C-terminal motifs of target proteins. Some of them also bind to internal PDZ binding motifs (PDZbms), but this aspect of the PDZ interactome is poorly studied. Here we explored internal PDZbm-mediated interactions using the PDZ domain of Shank1 as a model. We identified a series of human Shank1 ligands with C-terminal or internal PDZbms using proteomic peptide-phage display, and established that while the consensus sequence of C-terminal ligands is x-T-x-(L/F)-COOH, the consensus of internal PDZbm is exclusively x-T-x-F-x, where x is any amino acid. We found that the affinities of PDZbm interactions are in the low micromolar range. The crystal structure of the complex between Shank1 PDZ and an internal PDZbm revealed that the binding mode of internal PDZbms was similar to that of C-terminal ligands. Pull-down experiments confirmed that both C-terminal and internal PDZbm interactions can occur in the context of full-length proteins. Our study expands the interactome of Shank1 and hints at a largely unexplored interaction space of PDZ domains.
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