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There are two actin-binding sites in the gelsolin protein. These sites allow gelsolin to bind both along the side and at the end of an actin filament. Filaments that have been severed by gelsolin remain capped at their plus ends. Villin, an actin-bundling protein (see Figure 16-41A), is a member of the same protein family as gelsolin, but it has gained another actin-binding site and lost its ability to sever filaments except at very high (nonphysiological) Ca²⁺ concentrations.

Schematic domain structures are shown for homologous villidin proteins from D. discoideum (XP_636652, 1704 aa) and E. histolytica (“ABPH”, AF118397, 1602 aa). Both contain typical coronin domains at their amino termini in addition to 3 pleckstrin homology (PH), 3-5 gelsolin (G) and a villin headpiece (VHP) domains at the C-termini, all detected by matches to the corresponding hidden Markov models (HMM) from the PFAM database (http://www.sanger.ac.uk/Software/Pfam/).

The cleft between actin subdomains 1 and 3 is a hot spot for actin-binding proteins. A) Illustration of all the ABPs known to present and α-helix (shown in red) that interacts in the target-binding cleft in actin. An electrostatic surface representation of actin is shown on top of the ribbon diagram to illustrate the global hydrophobicity of the cleft. The structures shown are (counterclockwise): DBP,44 formin,24 gelsolin,15 WASP WH2 domain,22 and the Tβ domain.19^,20 The hydrophobic cleft is also targeted by marine toxins, such as kabiramide C and jaspisamide A.26 B,C) ADF/cofilin and actin are also predicted to interact in this cleft.

Reconstruction of the evolutionary history of proteins of the ADF/cofilin and gelsolin repeat families. The diagram is based on protein repertoires of selected representatives of each lineage: A. thaliana, P. falciparum, D. discoideum, S. cerevisiae (plus a severin-like protein of filamentous fungi absent in yeast) and H. sapiens. The eukaryotic genealogy is based on ref. 56. Proteins occurring in multiple isoforms are depicted only once. Based on structural similarity, the ADF domain and the gelsolin repeat might be descendants of an ancient actin-severing protein (proto ADF/GEL). Subsequent divergence, duplication and shuffling of additional domains and extensions gave rise to the diversity of ADF and GEL proteins of extant organisms, particularly unikonts. The ADF domain is duplicated in twinfilin, a protein that binds only G-actin and does not promote actin filament depolymerization; the duplication occurred apparently early after branching of eukaryotes into unikonts and bikonts. Around the same time, the coactosin/drebrin and the GMF (glia maturation factor) subfamilies arose. Its members bind only to F-actin and sometimes possess a characteristic C-terminal extension, such as the SH3 domain of Abp1. A very ancient multiplication of the ancestral GEL repeat gave rise to proteins with three gelsolin repeats such as those of D. discoideum (severin), filamentous fungi and Metazoa (CapG). It is intriguing that no proteins with a single (with the exception of Sec23/24 not depicted here; see text) or double repeat have subsisted. A further duplication generated proteins with 6 repeats (such as gelsolin), which then acquired extensions and additional domains, like leucine-rich repeats (LRR) (flightless of Metazoa) or a C-terminal villin headpiece (white rectangle) that conferred actin-bundling properties to some of them (villin and related proteins). In Amoebozoa a flightless-related protein resulted from the fusion of part of a flightess gene to a villin gene, whereas villidin resulted from the fusion of a coronin gene to a villin gene. In Amoebozoa also, frequently the first GEL domain of the tandem of six has been lost, and other domains have eroded so that they are difficult to recognize.