# SH3BGRL proteins are thioredoxin fold–containing actin filament pointed end capping proteins (TPECs)

## TL;DR

This paper reveals that SH3BGRL proteins help regulate actin filaments by capping their ends, using a thioredoxin fold in a non-enzymatic way.

## Contribution

The study identifies a new function for SH3BGRL proteins as non-enzymatic actin filament capping proteins with a thioredoxin fold.

## Key findings

- SH3BGRL proteins promote actin nucleation by stabilizing actin dimers and trimers.
- They inhibit actin subunit addition at the pointed end by directly associating with terminal subunits.
- SH3BGRL proteins can form a tripartite complex with actin and tropomodulin to enhance pointed end capping.

## Abstract

Cellular actin dynamics are tightly regulated by actin-binding proteins with specialized domains. Here, we identify SH3BGRL proteins as modulators of actin dynamics, characterized by their thioredoxin (Trx) fold and the absence of the canonical enzymatic site. The Trx fold is generally associated with enzymatic activity; however, in this context, it functions non-enzymatically to enhance actin nucleation, inhibit depolymerization and cap the growing pointed end of the actin filament. Our results indicate that all SH3BGRL isoforms weakly promote actin nucleation in vitro by stabilizing energetically unstable actin dimers and trimers. Using molecular dynamics simulations and assays that directly probe the pointed end of the actin filament, we show that SH3BGRL proteins efficiently inhibit actin subunit addition at the pointed end by direct association with the terminal actin subunits. However, SH3BGRL proteins are less effective at preventing subunit loss from the pointed end, but they can cooperate with tropomodulin to enhance this activity in an isoform-specific manner, indicating that all isoforms are capable of forming a tripartite complex with actin and tropomodulin. Based on our results, we propose a new and more appropriate name that reflects the function of the SH3BGRL protein family: thioredoxin fold–containing pointed end capping proteins (TPECs).

The online version contains supplementary material available at 10.1038/s41598-025-34096-y.