Structure of the human nonmuscle myosin 2A motor domain: Insights into isoform-specific mechanochemistry

TL;DR

This study reveals the structure of the human NM2A motor domain, explaining how differences in its sequence lead to specific cellular functions.

Contribution

The paper provides the first high-resolution structure of the human NM2A motor domain and identifies key sequence differences driving isoform-specific behavior.

Findings

The NM2A motor domain structure was resolved at 2.1 Å, revealing isoform-specific features.

Loop2 is identified as a critical region influencing functional specialization between NM2A and NM2B.

ATP binding is conserved across NM2 isoforms, but sequence variation affects actin-binding dynamics.

Abstract

Nonmuscle myosin 2A (NM2A) is the predominant myosin isoform in nonmuscle cells. Together with its paralogues NM2B and NM2C, NM2A enables tension and force generation, driving essential cellular processes such as membrane protrusion and retraction, directed migration, adhesion, and cytokinesis. The NM2 isoforms display paralogue-specific mechanochemical characteristics that support their specific cellular functions. Here, we determined the structure of the human NM2A motor domain, addressing a critical gap in understanding myosin family diversification. Based on our experimentally resolved 2.1 Å structure of the NM2A motor domain in its nucleotide-free state, we demonstrate, through integrative modeling of NM2-actin complexes and molecular dynamics simulations, how sequence differences between NM2A and NM2B underpin their functional specialization. Loop2 emerges as a critical determinant of isoform-specific behavior. Comparative analysis of ATP interaction fingerprints across NM2 isoforms reveals a conserved ATP binding mechanism. These findings illuminate an allosteric energy transduction pathway that connects sequence variation to actin-binding dynamics, providing mechanistic insight into isoform-specific cytoskeletal functions.

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