# Spatial Organization in Biochemical Reaction Networks

> **NIH NIH R35** · UNIVERSITY OF WASHINGTON · 2024 · $373,212

## Abstract

Project Abstract
This proposal seeks to understand how biochemical networks organize specific reactions in space
and time, with a focus on regulatory mechanisms in cell signaling and gene expression. We aim
to develop biochemical model systems to understand how cells direct kinase activity in complex,
interconnected signaling networks and to engineer tools to study structure-function relationships
in eukaryotic genomes. These efforts will help us to dissect the mechanistic features that enable
precise spatial and temporal control over biochemical reactions, provide new strategies to
engineer cellular functions, and inform the design of more effective therapeutics that target
specific cellular processes. In cell signaling, scaffold proteins coordinate the formation of physical
complexes that assemble multiple signaling proteins. Scaffold proteins are widely assumed to act
by tethering proteins together to accelerate specific reactions. Recent mechanistic and structural
studies, however, have revealed unexpectedly complex biochemical mechanisms that regulate
signaling through conformational changes and allosteric effects. This complexity is likely
magnified in cellular environments, where multiple pathways compete for shared components and
a plethora of different regulatory factors perform functions that are poorly understood at the
molecular level. In particular, we currently lack a mechanistic framework to understand how
scaffold-mediated kinase reactions are affected by competing scaffolds, phosphatases, and
accessory proteins that assemble higher-order complexes. Addressing this knowledge gap with
quantitative kinetic frameworks, functional models and structural studies is critical for
understanding how cells precisely process and integrate different signaling inputs to achieve
specific outcomes. Conceptually-related questions arise in genome regulation, where spatial
organization also plays a central role. Eukaryotic genomes adopt 3D structures that appear to
promote specific biochemical processes by positioning genes in proximity to remote DNA
regulatory sites or to localized proteins, but this model has not been rigorously tested. A major
challenge is the lack of robust tools to systematically perturb genome structures and assess
effects on function. Recent CRISPR-Cas methods show promise but have not yet been widely
adopted, possibly due to limited efficacy and generalizability. Developing more robust tools to
systematically perturb genome structure will enable us to address critical knowledge gaps in the
relationship between genome structure and function.

## Key facts

- **NIH application ID:** 10896392
- **Project number:** 5R35GM124773-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Jesse George Zalatan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $373,212
- **Award type:** 5
- **Project period:** 2017-08-10 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10896392

## Citation

> US National Institutes of Health, RePORTER application 10896392, Spatial Organization in Biochemical Reaction Networks (5R35GM124773-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10896392. Licensed CC0.

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