# How Leiomodin and Tropomodulin use a common fold for different actin assembly functions

## TL;DR

This paper explores how two similar proteins, Tropomodulins and Leiomodins, evolved to perform different roles in building actin filaments.

## Contribution

The study reveals that functional differences arise from structural adaptations in conserved domains, not from unique extensions.

## Key findings

- Tmods and Lmods have similar but distinct localization in sarcomeres and do not compete biochemically.
- Lmods' nucleation function depends on the loss of capping elements and the specialization of the ABS2 domain.
- The WH2 domain in Lmods plays an auxiliary role in nucleation rather than being essential.

## Abstract

How proteins sharing a common fold have evolved different functions is a fundamental question in biology. Tropomodulins (Tmods) are prototypical actin filament pointed-end-capping proteins, whereas their homologs, Leiomodins (Lmods), are powerful filament nucleators. We show that Tmods and Lmods do not compete biochemically, and display similar but distinct localization in sarcomeres. Changes along the polypeptide chains of Tmods and Lmods exquisitely adapt their functions for capping vs. nucleation. Tmods have alternating tropomyosin (TM)- and actin-binding sites (TMBS1, ABS1, TMBS2, ABS2). Lmods additionally contain a C-terminal extension featuring an actin-binding WH2 domain. Unexpectedly, the different activities of Tmods and Lmods do not arise from the Lmod-specific extension. Instead, nucleation by Lmods depends on two major adaptations – the loss of pointed-end-capping elements present in Tmods and the specialization of the highly conserved ABS2 for recruitment of two or more actin subunits. The WH2 domain plays only an auxiliary role in nucleation.