# Structural and functional studies of protein kinase C regulation

> **NIH NIH R01** · TEXAS A&M AGRILIFE RESEARCH · 2021 · $306,278

## Abstract

Protein Kinases C (PKC) define a family of lipid-activated kinases that are key effectors of phosphoinositide
signaling – a major intracellular signaling pathway of eukaryotic cells. Consistent with this central activity,
dysregulation of PKC signaling is implicated in cancer progression, cardiac disease, diabetes, and Alzheimer's
disease. Because of the fundamental role of PKC in signal transduction, the development of modulators of
PKC activity – both for therapeutic and basic research purposes – is widely recognized as one of the major
challenges in the field. Addressing these challenges requires an atomic-level understanding of PKC control –
in particular, how lipids regulate PKC activity. This subject defines a major gap in understanding of PKC
regulatory mechanisms. The central objective of this research proposal is to decipher the mechanism of the
key event that triggers activation of PKC – its interaction with diacylglycerol (DAG). It is currently unknown
how DAG is recognized and captured in membranes by the conserved homology 1 (C1) domains of PKC. To
address this critical gap in knowledge, a synergistic combination of advanced solution NMR approaches,
atomistic molecular dynamics simulations, and biochemical strategies will be applied to address the following
Specific Aims: (1) to understand the molecular basis of diacylglycerol recognition by C1 domains, (2) to
decipher precisely how C1 domains are initially recruited to membranes, and (3) to determine how tandem C1
domains execute a coincidence detection of DAG and anionic phospholipids. Insights into the DAG-sensing
mechanism obtained from the proposed studies will have impact that extends beyond the already large
problem of PKC regulation. The atomic-level information regarding C1-DAG interactions will be directly
applicable to five other large families of signaling proteins that rely on C1 domains for regulation of their DAG-
dependent activities. This information will also facilitate the design of pharmacological agents for rational
modulation of PKC function by direct targeting of its C1 domains.

## Key facts

- **NIH application ID:** 10210841
- **Project number:** 2R01GM108998-06
- **Recipient organization:** TEXAS A&M AGRILIFE RESEARCH
- **Principal Investigator:** Tatyana I. Igumenova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $306,278
- **Award type:** 2
- **Project period:** 2014-09-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210841

## Citation

> US National Institutes of Health, RePORTER application 10210841, Structural and functional studies of protein kinase C regulation (2R01GM108998-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210841. Licensed CC0.

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