# Immunodiversity of plant receptor kinase networks for synthetic circuit design

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $379,038

## Abstract

PROJECT SUMMARY
Immune systems across kingdoms of life recognize pathogen-associated molecules through germline-encoded
innate immune receptors. Receptor repertoires in plants have evolved to detect an especially diverse set of
ligands due to massive expansion of the receptor kinase gene family with specialized ligand recognition
functions. Pairing receptor sequence diversity with specific recognition functions across 100 million RK genes
(350,000 plant species * 500 receptors per genome) is a grand challenge in plant molecular biology. It also
presents the opportunity to develop a new class of protein-based sensors for biotechnology. The Steinbrenner
lab aims to characterize and deploy this vast plant immunodiversity for ligand-induced modulation of
engineered signaling pathways.
First, we will define the full ligand space that is monitored by plant receptors by focusing on the large subfamily
of leucine-rich repeat receptor kinases (termed receptors here) which bind small peptide epitopes to initiate
immune signaling. We will combine evolution- and structure-guided approaches to decode the basis of
receptor:ligand specificity, including an extensive phylogenomic analysis, peptide variant libraries, and
ancestral sequence reconstruction. We hypothesize that transitions in ligand specificity are marked by amino
acid substitutions in predicted ligand binding sites among ancestral receptor genes. For “orphan” receptors
lacking defined functions, we will conduct a genomic screen using synthetic DNA libraries encoding candidate
pathogen epitopes using both plant and yeast models as reporters for receptor activation. We hypothesize that
most receptors involved in plant innate immunity will be activated by specific pathogen-derived peptide
sequences. Combined, these approaches will provide basic insights into receptor:ligand specificity as well as a
toolkit of extracellular sensor domains responsive to specific peptide agonists.
Second, we will leverage the unique network architecture of plant immune networks to engineer synthetic
signaling pathways that do not interfere with endogenous animal signaling pathways. The plant receptors
studied here signal through heterodimerization with a common co-receptor called BAK1. Co-receptor activation
culminates in phosphorylation of substrates based on defined phosphocode motifs. We are currently
engineering the human inflammation signaling pathway to accept orthogonal input from plant receptors by
incorporating plant kinase substrates into specific, phosphoregulated signaling factors. In parallel, we will use
plant receptor:co-receptor heterodimerization as a platform to scaffold endogenous human immune signaling
domains from Toll-like receptors. We hypothesize that engineered pathways will allow modular tuning by
diverse peptide ligands, providing an alternative to current immunoglobulin or GPCR-based synthetic tools. In
summary our lab is poised to deploy tools for receptor de-orphanization and signaling pathw...

## Key facts

- **NIH application ID:** 10890041
- **Project number:** 5R35GM151272-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Adam D Steinbrenner
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,038
- **Award type:** 5
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890041

## Citation

> US National Institutes of Health, RePORTER application 10890041, Immunodiversity of plant receptor kinase networks for synthetic circuit design (5R35GM151272-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890041. Licensed CC0.

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