# Structural and Functional Studies of Teneurins: A bacterial toxin homolog in human

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $324,000

## Abstract

Project Summary
The interplay between cellular adhesion and cellular signaling is essential for the development of all organs
such as the brain, and for the functioning of systems such as the nervous systems. Teneurins (TEN1-4) are a
poorly understood family that mediates intercellular communication. They have essential roles in embryonic
development and neural circuit-wiring; and are linked to numerous human diseases including neurological
disorders and cancers. TENs are type-II membrane proteins with large C-terminal extracellular regions (ECR)
that majorly exhibit no identifiable domains. The ECR mediates trans-cellular heterophilic interaction of TENs
with Latrophilins(LPHN1-3), a family of G-Protein Coupled Receptors; to regulate synapse function. The ECR
also mediates trans-cellular homophilic interaction of TENs with themselves to instruct neural circuit-wiring.
However, the molecular mechanisms underlying TEN action remains poorly understood majorly due to the
lack of structural information on the ECR. We recently laid the groundwork by determining the high-resolution
cryo-EM structure of the TEN2 ECR and revealed a surprising homology to bacterial Tc-toxins. We also
showed that an alternatively spliced insert acts as a switch to regulate LPHN binding and other TEN functions
such as synapse formation. The ultimate goal of the research proposed in this application is to understand the
mechanical details of various TEN functions that are mediated by its ECR. We propose three Specific Aims that
are based on the major unknowns in TEN function and a Follow-up Aim to perform structure/function
relationship studies: First, we aim to understand the molecular details of the TEN/LPHN interaction. Second,
we aim to understand the molecular determinants for the trans-homodimerization of TEN. Third, we aim to
reveal whether TEN functions via autoproteolysis similar to bacterial toxins. Then, we aim to use the
information from the first three aims to study TEN function in synapse formation assays. This research has a
multi-disciplinary approach where the structural and functional data performed in the PI's lab range from
electron microscopy, biophysical and biochemical methods, neuronal assays to cell-biology and is
complemented by the expertise provided or performed by the laboratories of close collaborators. The proposed
experiments will build on exciting results, including the very unusual TEN2 structure, surprising involvement
of alternative splicing in TEN function, key advances in the purification of all needed TEN fragments, and the
observation of proteolytic products. We expect that this research will provide critical insights into the
mechanistic details of TEN function, helping to establish novel principles on intercellular communication that
are vital for numerous cellular functions.

## Key facts

- **NIH application ID:** 10474368
- **Project number:** 5R01GM134035-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Demet Arac-Ozkan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $324,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474368

## Citation

> US National Institutes of Health, RePORTER application 10474368, Structural and Functional Studies of Teneurins: A bacterial toxin homolog in human (5R01GM134035-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474368. Licensed CC0.

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