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Leveraging coevolutionary insights and AI-based structural modeling to unravel receptor-peptide ligand-binding mechanisms.
Snoeck, Simon; Lee, Hyun Kyung; Schmid, Marc W; Bender, Kyle W; Neeracher, Matthias J; Fernández-Fernández, Alvaro D; Santiago, Julia; Zipfel, Cyril.
Afiliação
  • Snoeck S; Department of Plant and Microbial Biology (IPMB), Zurich-Basel Plant Science Center, University of Zurich, Zurich 8008, Switzerland.
  • Lee HK; The Plant Signaling Mechanisms Laboratory, Department of Plant Molecular Biology, University of Lausanne, Lausanne 1015, Switzerland.
  • Schmid MW; MWSchmid GmbH, Glarus 8750, Switzerland.
  • Bender KW; Department of Plant and Microbial Biology (IPMB), Zurich-Basel Plant Science Center, University of Zurich, Zurich 8008, Switzerland.
  • Neeracher MJ; Department of Plant and Microbial Biology (IPMB), Zurich-Basel Plant Science Center, University of Zurich, Zurich 8008, Switzerland.
  • Fernández-Fernández AD; Department of Plant and Microbial Biology (IPMB), Zurich-Basel Plant Science Center, University of Zurich, Zurich 8008, Switzerland.
  • Santiago J; The Plant Signaling Mechanisms Laboratory, Department of Plant Molecular Biology, University of Lausanne, Lausanne 1015, Switzerland.
  • Zipfel C; Department of Plant and Microbial Biology (IPMB), Zurich-Basel Plant Science Center, University of Zurich, Zurich 8008, Switzerland.
Proc Natl Acad Sci U S A ; 121(33): e2400862121, 2024 Aug 13.
Article em En | MEDLINE | ID: mdl-39106311
ABSTRACT
Secreted signaling peptides are central regulators of growth, development, and stress responses, but specific steps in the evolution of these peptides and their receptors are not well understood. Also, the molecular mechanisms of peptide-receptor binding are only known for a few examples, primarily owing to the limited availability of protein structural determination capabilities to few laboratories worldwide. Plants have evolved a multitude of secreted signaling peptides and corresponding transmembrane receptors. Stress-responsive SERINE RICH ENDOGENOUS PEPTIDES (SCOOPs) were recently identified. Bioactive SCOOPs are proteolytically processed by subtilases and are perceived by the leucine-rich repeat receptor kinase MALE DISCOVERER 1-INTERACTING RECEPTOR-LIKE KINASE 2 (MIK2) in the model plant Arabidopsis thaliana. How SCOOPs and MIK2 have (co)evolved, and how SCOOPs bind to MIK2 are unknown. Using in silico analysis of 350 plant genomes and subsequent functional testing, we revealed the conservation of MIK2 as SCOOP receptor within the plant order Brassicales. We then leveraged AI-based structural modeling and comparative genomics to identify two conserved putative SCOOP-MIK2 binding pockets across Brassicales MIK2 homologues predicted to interact with the "SxS" motif of otherwise sequence-divergent SCOOPs. Mutagenesis of both predicted binding pockets compromised SCOOP binding to MIK2, SCOOP-induced complex formation between MIK2 and its coreceptor BRASSINOSTEROID INSENSITIVE 1-ASSOCIATED KINASE 1, and SCOOP-induced reactive oxygen species production, thus, confirming our in silico predictions. Collectively, in addition to revealing the elusive SCOOP-MIK2 binding mechanism, our analytic pipeline combining phylogenomics, AI-based structural predictions, and experimental biochemical and physiological validation provides a blueprint for the elucidation of peptide ligand-receptor perception mechanisms.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arabidopsis / Proteínas de Arabidopsis Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Arabidopsis / Proteínas de Arabidopsis Idioma: En Ano de publicação: 2024 Tipo de documento: Article