# Natural and synthetic mechanisms of ligand formation

> **NIH NIH R35** · UNIVERSITY OF TEXAS DALLAS · 2024 · $376,000

## Abstract

PROJECT SUMMARY/ABSTRACT
Cells tightly regulate secreted signaling proteins so that they function at the right place and time. Most signaling
proteins form complexes with other signals in various combinations. This mix-and-match strategy is deployed in
all stages of metazoan evolution, ultimately enabling cell type diversity and complex animal behaviors. But what
are the molecular rules that govern the formation of signaling ligands? The overarching goal of my research
program is to describe the fundamental mechanisms of signal assembly and processing, as well as to provide
solutions when signaling goes awry. The first arm of the program investigates transforming growth factor-beta
signaling proteins, Vg1 and Nodal, that must assemble as heterodimers to properly induce the mesoderm and
endoderm tissues (e.g., muscle, bone, blood). We recently discovered that several chaperones aid in the robust
and selective assembly of Vg1-Nodal heterodimers in animal embryos. This finding has opened fundamental
mechanistic questions on chaperone-mediated signal assembly: What are the molecular rules (and the order of
these rules) that chaperones use to control the composition of signaling complexes? We will combine
embryological manipulation, biochemical reconstitution in vitro, and computational modeling to identify the
protein regulators and binding motifs that govern the heteromeric assembly of signaling proteins. In the second
arm of the program, we aim to assign the true physiological function of endogenous peptides. For example, a
single polyprotein-encoding gene can produce up to eight bioactive peptides. However, cells only use a handful
of convertases to process the thousands of secreted precursor proteins and peptides. In our previous work, we
established a new molecular approach to process secreted proteins, the Synthetic Processing (Synpro) system.
The Synpro system is composed of a family of secreted, synthetic proteases that can cleave cognate sequences
on any secreted protein. We will further develop these novel secreted proteases to cleave secreted polyproteins
in a sequence-specific way. Using the Synpro system, our lab will assign peptide function in two ways: (i)
introduction of Synpro-cleavable sequences into polyproteins or (ii) directed evolution of Synpro proteases to
process the natural sequence of each peptide within a polyprotein. Diversifying the cleavage sequence alphabet
of Synpro proteases will enable us to assign peptide function, deconstruct complex behaviors, and disrupt
diseases that arise from secreted signaling proteins.

## Key facts

- **NIH application ID:** 10881990
- **Project number:** 5R35GM150967-02
- **Recipient organization:** UNIVERSITY OF TEXAS DALLAS
- **Principal Investigator:** Polimyr Caesar Dave Pelisco Dingal
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $376,000
- **Award type:** 5
- **Project period:** 2023-07-07 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881990

## Citation

> US National Institutes of Health, RePORTER application 10881990, Natural and synthetic mechanisms of ligand formation (5R35GM150967-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10881990. Licensed CC0.

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