# Structure and function of DISC1 in the cAMP pathway

> **NIH NIH R01** · IOWA STATE UNIVERSITY · 2021 · $324,936

## Abstract

DISC1 (Disrupted-In-Schizophrenia-1) has emerged as a significant genetic risk factor for a wide
range of mental illness such as schizophrenia, bipolar disorders and depression. The product of DISC1 is
a long scaffold protein that plays a critical role in several neuronal signaling pathways. Despite growing
appreciation of its role in the etiology of mental disorders, almost nothing is known about the structure of
DISC1 and its mechanisms of interaction and regulation. This research project will specifically focus on the
role of DISC1 in the cAMP pathway. Reduced cAMP levels are found in patients suffering from major
depression and are associated with neurodegenerative diseases. Enzymes controlling intracellular levels
of cAMP, such as the phosphodiesterase family PDE4, have considerable pharmaceutical importance for
the development of antidepressant and memory enhancing drugs. The overall goal of this project is to
provide a structural framework describing the role of DISC1 in the cAMP pathway and to understand how
alterations in this pathway contribute to the etiology of psychiatric disorders. Aim 1 will provide a complete
structural model of DISC1, including its mechanism of oligomerization and modulation by phosphorylation.
We will also investigate the structural consequences of disease-associated mutations. We are proposing
here an integrative structural approach combining Hydrogen-Deuterium Exchange Mass Spectrometry
(HDX-MS), solution NMR spectroscopy, X-ray crystallography, Small-angle X-ray Scattering (SAXS) and
molecular simulations to reconstitute the complete structural and dynamical features of DISC1. Our
preliminary data demonstrate that we can characterize DISC1 N-terminal constructs by solution NMR
spectroscopy while constructs encompassing the central and/or C-terminal domains are well suited for X-
ray crystallography study. Aim 2 will combine biochemical and structural approaches to characterize the
interaction between DISC1 and ATF4, a major transcription factor the cAMP pathway controlling the
expression of the CRE-elements and of the phosphodiesterase PDE4D9. Our preliminary data show that
DISC1-ATF4 complex can be reconstituted in vitro with truncated constructs of both proteins. This aim will
provide a mechanistic framework for understanding the role of DISC1 as transcriptional co-repressor and
the function of DISC1-ATF4 complex in the cAMP pathway. Aim 3 will unravel the mechanisms of allosteric
inhibition of long and short PDE4 isoforms by DISC1, using a combination of biochemical, structural and
computational techniques. Overall, completion of this project will provide a comprehensive, unifying
framework for understanding the role of DISC1 in the cAMP pathway. Our work will also provide new
structural targets for the development of molecules regulating cAMP levels.

## Key facts

- **NIH application ID:** 10240637
- **Project number:** 5R01GM132561-03
- **Recipient organization:** IOWA STATE UNIVERSITY
- **Principal Investigator:** Julien Roche
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $324,936
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10240637

## Citation

> US National Institutes of Health, RePORTER application 10240637, Structure and function of DISC1 in the cAMP pathway (5R01GM132561-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10240637. Licensed CC0.

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