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Review
. 2020 Jul 1;9(7):1590.
doi: 10.3390/cells9071590.

Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function

Cláudia Brito  1   2 , Sandra Sousa  1
Affiliations
Review

Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function

Cláudia Brito et al. Cells. .

Abstract

Non-muscle myosin 2A (NM2A) is a motor cytoskeletal enzyme with crucial importance from the early stages of development until adulthood. Due to its capacity to convert chemical energy into force, NM2A powers the contraction of the actomyosin cytoskeleton, required for proper cell division, adhesion and migration, among other cellular functions. Although NM2A has been extensively studied, new findings revealed that a lot remains to be discovered concerning its spatiotemporal regulation in the intracellular environment. In recent years, new functions were attributed to NM2A and its activity was associated to a plethora of illnesses, including neurological disorders and infectious diseases. Here, we provide a concise overview on the current knowledge regarding the structure, the function and the regulation of NM2A. In addition, we recapitulate NM2A-associated diseases and discuss its potential as a therapeutic target.

Keywords: NM2A activity regulation; NM2A filament assembly; actomyosin cytoskeleton; cell adhesion; cell migration; non-muscle myosin 2A (NM2A); plasma membrane blebbing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Phylogenetic tree of the myosin superfamily in humans. The 38 human genes that encode the diverse myosins are identified. The sequences of the myosin motor domains were analyzed and grouped phylogenetically allowing the distribution of myosins into 12 different classes. This figure was adapted from [8].
Figure 2
Figure 2
The structure of non-muscle myosin 2 (NM2). (A) NM2 is a hexamer composed by two heavy chains (green) and four light chains: Two regulatory (RLC, pink) and two essential light chains (ELC, yellow). The full NM2 complex can be structurally divided in three regions: The motor, the neck and the tail domains. The head domain includes the ATP- and actin-binding sites. The light chains associate with the heavy chains in the neck domain. The heavy meromyosin (HMM) is an NM2 fragment obtained by tryptic digestion and commonly used in in vitro biochemical assays. Even lacking part of the tail, HMM maintains the structure and the biochemical properties of the full molecule. (B) Schematic representation of the inactive NM2 molecule. Unphosphorylated RLC (light pink) promotes the intramolecular interaction between the tail and the motor domain. The phosphorylation of RLC Serine 19 by Myosin light chain kinase (MLCK) turns on NM2, promoting the assembly of filaments and increasing ATPase activity.
Figure 3
Figure 3
Mechanism of NM2 assembly and binding to actin filaments. (A) Assembly of homotypic bipolar filaments of NM2A. NM2A molecules interact antiparallelly by their tail regions and assemble into NM2A bipolar filaments of around 300 nm in length. The NM2A motor domains are oriented to the outside of the polymer and are free to interact with polymerized actin. (B) NM2A polymers bind to actin filaments building up stress fibers or more dynamic cross-linked actomyosin meshworks. (C) Assembly of heterotypic bipolar filaments. Different myosins are able to co-polymerize originating mixed filaments which may have different kinetic properties. Extra domains of Myo18A (purple, PDZ domain) may allow the interaction with additional proteins possibly increasing the layers of NM2 regulation.
Figure 4
Figure 4
Schematic model for NM2-dependent actin sliding cycle. ATP binding dissociates NM2 from actin (actin release). Myosin motor head hydrolyzes ATP and re-attaches to actin. The release of the phosphate (Pi) triggers a conformational change that promotes movement and powers the contraction of actin filaments (powerstroke). The colored region corresponds to the portion of the cycle during which the NM2 motor head is strongly bound to actin, this is called duty ratio. The exchange of ADP by ATP restarts the cycle. This figure was adapted from [65].
Figure 5
Figure 5
Multiple mechanisms regulate NM2A activity and subcellular localization. NM2A activation (pink arrows) and inactivation (yellow arrows) are mainly regulated through RLC phosphorylation or dephosphorylation on Ser, Thr and Tyr residues. Events occurring at the NM2A tail, such as phosphorylations (green arrows), interaction with binding partners and co-polymerization of heterotypic filaments, control the assembly and disassembly of NM2 filaments. Regulation through the head domain is determined by the differential binding of NMHC2 to distinct actin isoforms.
Figure 6
Figure 6
Involvement of NM2A in cell migration and plasma membrane blebbing. (A) Scheme showing a cell migrating in a 2D environment, top and lateral views are represented. To migrate in a 2D environment the cell polarizes in the front and rear regions, which are defined by an intracellular gradient of proteins and allow directionality during movement. NM2 isoforms play a key role in 2D migration and are selectively localized at different cell regions. NM2A concentrates at the cell front where high actin dynamics are taking place, and gradually decreases towards the rear where NM2B is concentrated. In between cell poles (front and rear) NM2A and NM2B co-exist at different concentrations in mixed actomyosin filaments. Focal adhesions at the extremities of stress fibers are shown as blue circles. (B) Process of plasma membrane bleb formation and retraction. Upon stimuli (e.g., apoptosis and calcium influx), a membrane protrusion forms (bleb initiation) due to the plasma membrane detachment from the cortical cytoskeleton. As a result of intracellular pressure, the bleb swells (bleb expansion) until ezrin recruits cytoskeletal proteins that promote actin polymerization and the subsequent interaction with NM2A. NM2A contractile forces pull the membrane inwards and support bleb retraction.
Figure 7
Figure 7
Human pathologies associated with mutations in MYH9, NM2A expression and/or activity defects. In agreement with the key roles of NM2A from embryo development to adulthood, its malfunction affects several organs causing mild to life-threatening disorders. In particular, NM2A defects were associated with neurodegenerative diseases, cancer, bleeding diseases and kidney inflammation.
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