Structural and functional mechanisms of actin isoforms

Fig. 1. Structures of G‐ and F‐actin. (A) Structure of G‐actin (PDB ID: 1ATN). The actin monomer structure is shown in cartoon and transparent surface representation. Ca2+ and ATP in the active site are shown. The four actin subdomains (SD1 to SD4), the nucleotide‐binding cleft, the barbed end groove, and the D‐loop are indicated. Ca2+ is shown as a green sphere. (B) Superimposition of the actin monomer structures of skeletal muscle α‐actin (PDB ID: 8DMX, blue), cardiac muscle α‐actin (PDB ID: 8DMY, purple), β‐actin (PDB ID: 8DNH, red), and γ‐actin (PDB ID: 8DNF, yellow). The positions of the divergent N‐termini are indicated with an asterisk. (C) Actin protomers are indicated in flat surface representation. The protomers located towards the pointed end are indicated as (a − 1), (a − 2), and the protomer on the barbed end is indicated as (a + 1). Subdomains 1–4 are indicated as SD1–SD4. (D) Cryo‐EM structure of F‐actin (PDB ID: 8DMX). Four actin protomers are shown in cartoon representation. The pointed and barbed ends, actin subdomains, Mg2+ (green sphere), nucleotides (dark red spheres), the N‐terminus, and the D‐loop are indicated.

Fig. 2. N‐terminal processing and PTMs in actin isoforms. (A) N‐terminal processing in the N‐terminus region of actin isoforms. Conserved amino acids are shown in black, and variable amino acids are shown in pink. Amino acids that are absent in mature actin isoforms due to proteolytic cleavage are shown in gray. (B) Different actin isoform species are produced by N‐terminal processing. Nt‐acetylation (Ac‐) and Nt‐arginylation (R‐) are shown in pink. Amino acids that are absent due to proteolytic cleavage are shown in gray. The dash (−) indicates a gap in the alignment. (C) Locations of selected PTMs in the actin filament are shown in the F‐actin structure (PDB ID: 8DNF). Acetylated lysine residues are shown in gray spheres and oxidized methionine residues are shown in pink spheres in each protomer.

Fig. 3. Location of selected mutations in actin isoform structures. (A) Select mutations (n > 4) in skeletal muscle α‐actin mapped onto its structure (PDB ID: 8DMX). For clarity, only one protomer is highlighted in dark gray color. (B) Select mutations (n > 4) in cardiac muscle α‐actin mapped onto its structure (PDB ID: 8DMY). For clarity, only one protomer is highlighted in pink color. (C) Select mutations (n > 2) in β‐actin mapped onto its structure (PDB ID: 8DNH). For clarity, only one protomer is highlighted in blue color. (D) Select mutations (n > 4) in γ‐actin mapped onto its structure (PDB ID: 8DNF). ‘n’ indicates the number of studies that showed mutations of the indicated amino acids. For clarity, only one protomer is highlighted in green color. (E) Superimposition of the cryo‐EM structures of filamentous skeletal muscle α‐actin structure (PDB ID: 8DMX), cardiac muscle α‐actin structure (PDB ID: 8DMY), β‐actin (PDB ID: 8DNH), and γ‐actin (PDB ID: 8DNF) show the location of disease‐causing mutations (n > 4) in muscle actins (orange spheres) and non‐muscle actins (turquoise spheres) relative to the short‐pitch axis (green). Four highlighted actin protomers from A to D are shown.…