Journal Article

Capping protein regulators fine-tune actin assembly dynamics

Edwards, Marc, Schafer, Dorothy A., Zwolak, Adam, Dominguez, Roberto, Sept, David, Cooper, John A.

2014

Overview

Key Points Capping protein (CP) is a major regulator of actin assembly dynamics via the capping of actin filament barbed ends. The capping activity of CP can be regulated by a number of different proteins and phospholipids in various ways, some direct and others indirect. The capping protein interacting (CPI) motif is a 30-amino acid region necessary and sufficient to bind and inhibit CP. This motif is found in a set of unrelated proteins, many of which are involved in membrane interactions. CARMIL (capping protein, ARP2/3 and myosin I linker) family proteins contain a CPI motif, and they also contain a separate CARMIL-specific interacting (CSI) motif. In CARMIL, the CPI motif is necessary for distinct cellular functions, such as macropinocytosis. The CPI and CSI motifs are unstructured in the unbound state, but they adopt a specific structure when they bind to CP, applying themselves to the surface of CP. The CPI and CSI motifs decrease the actin capping activity of CP via an allosteric mechanism. The complex of a CPI motif-containing protein with CP retains a low level of capping activity, which raises the possibility that CPI motif-containing proteins may target CP to certain cellular locations, in addition to, or as an alternative to, simply decreasing the capping activity. Vertebrates have three distinct conserved CARMIL genes, which seem to have distinct functions in cells. Of note, CARMIL2 localizes with vimentin filaments, representing a potential novel link between the actin and intermediate filament cytoskeleton systems. The actin capping activity of capping protein (CP) is indirectly regulated by competing with other factors for filament binding, or directly by factors that bind CP and sterically inhibit its interactions with filaments. Other proteins interact with CP through their 'capping protein interaction' (CPI) motif and modulate its activity via allosteric effects. Capping protein (CP) binds the fast growing barbed end of the actin filament and regulates actin assembly by blocking the addition and loss of actin subunits. Recent studies provide new insights into how CP and barbed-end capping are regulated. Filament elongation factors, such as formins and ENA/VASP (enabled/vasodilator-stimulated phosphoprotein), indirectly regulate CP by competing with CP for binding to the barbed end, whereas other molecules, including V-1 and phospholipids, directly bind to CP and sterically block its interaction with the filament. In addition, a diverse and unrelated group of proteins interact with CP through a conserved 'capping protein interaction' (CPI) motif. These proteins, including CARMIL (capping protein, ARP2/3 and myosin I linker), CD2AP (CD2-associated protein) and the WASH (WASP and SCAR homologue) complex subunit FAM21, recruit CP to specific subcellular locations and modulate its actin-capping activity via allosteric effects.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/80/84/1372 / 631/80/84/1756 / Actin / Actin Capping Proteins - metabolism / Actin Capping Proteins - physiology / Actin Cytoskeleton - physiology / Adaptor Proteins, Signal Transducing - metabolism / Adaptor Proteins, Signal Transducing - physiology / Amino Acid Sequence / Biochemistry / Biology / Cancer Research / Carrier Proteins - metabolism / Carrier Proteins - physiology / Cell Biology / Cellular control mechanisms / Cytoskeletal Proteins - metabolism / Cytoskeletal Proteins - physiology / Developmental Biology / DNA-Binding Proteins - metabolism / DNA-Binding Proteins - physiology / Genetic aspects / Humans / Kinases / Life Sciences / Membranes / Microfilament Proteins - metabolism / Microfilament Proteins - physiology / Models, Molecular / Phosphatidylinositol Phosphates - chemistry / Physiology / Properties / Protein Binding / Protein biosynthesis / Protein Conformation / Protein research / Proteins / review-article / Stem Cells