# Structural Co-evolution of the LARP Superfamily and its Role in Functional Plasticity

> **NIH NIH R35** · FLORIDA STATE UNIVERSITY · 2022 · $88,081

## Abstract

PROJECT SUMMARY/ABSTRACT
The long-term goal of our research program is to decipher the molecular mechanism of “non-canonical” protein-
RNA interactions studying a particularly fascinating and disease-relevant family of proteins, called the La-related
protein (LARP) superfamily, on a molecular level. Cytoplasmic LARPs play a pivotal role in post-transcriptional
gene control by regulating the delicate balance between active translation, degradation, and storage of mRNAs.
Hence, many LARPs are intimately implicated in various cancers and fibroproliferative diseases rendering them
an important class of druggable targets. However, the development of therapies has been stunted by the lack of
detailed molecular-level information. Our research will elucidate the molecular mechanism of RNA recognition
exhibited by LARPs, in particular, to explain the intricacies of commonality and individuality, i.e. how their com-
mon RNA-binding motif, called the La-module, has individually evolved to allow specific RNA recognition and
thus achieve its distinct function. The investigation is based on our unique strength in solution and solid-state
NMR spectroscopy and their close coupling with other biochemical, biophysical, computational, and functional
approaches. Our initial efforts will follow two lines of inquiry, simultaneously focusing on two members of the
LARP superfamily, hLARP6 and hLARP1. In the first line of inquiry, we will explore how the La-module of hLARP6
achieves the exclusive recognition of the highly conserved 5' stem-loop (5'SL) motif, which is found in all verte-
brate mRNAs encoding type I collagens. This line of study will provide a detailed molecular-level map on how
individual elements of the La-module contribute to the specificity and affinity of 5'SL binding. The detailed insights
to be gained, together with currently available biochemical and biophysical data, will provide essential insights
into the molecular “symbiosis” of the individual elements of the La-module and close this critical gap in knowledge
required for the development of therapeutic strategies against fibroproliferative diseases. In the second line of
inquiry, we will analogously dissect how the La-module of hLARP1 recognizes a distinctly different type of RNA
compared to hLARP6. hLARP1 was found to be heavily involved in proliferation and cell cycle defects and to be
significantly upregulated in malignant cells and tissues. Very recent biochemical studies revealed that the La-
module of hLARP1 sequentially binds to the 3' poly(A) and then to the 5ʹ terminal oligopyrimidine (5ʹTOP) motifs
of mRNAs. Notably, this peculiar two-step behavior has not yet been observed for any other LARP. We will
uncover this unusual molecular mechanism by investigating the structural and dynamic changes of hLARP1
upon binding of the poly(A) and 5'TOP motifs. This study will for the first time reveal how the initial binding of
one RNA to its La-module elicits structural and dynamic changes requir...

## Key facts

- **NIH application ID:** 10680100
- **Project number:** 3R35GM142912-02S1
- **Recipient organization:** FLORIDA STATE UNIVERSITY
- **Principal Investigator:** Robert Silvers
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $88,081
- **Award type:** 3
- **Project period:** 2021-09-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10680100

## Citation

> US National Institutes of Health, RePORTER application 10680100, Structural Co-evolution of the LARP Superfamily and its Role in Functional Plasticity (3R35GM142912-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10680100. Licensed CC0.

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