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The Gelsolin Family
A group of actin binding proteins, sharing  repeats of about 15kDa homologous domains (Way & Weeds, 1988) that adopt a similar fold (Burtnick et al, 1999).  The gelsolins typically sever and cap actin filaments in a Ca2+, pH and phospholipid dependent manner and are involved in cell structure, motility, apoptosis, amyloidosis and cancer.  Gelsolin is a very well studied protein yet surprises continue to be discovered in its structure and its function.  Many proteins exist that show homology to the gelsolins. 

Contents:-
Gelsolin N to C terminus cold to warm colours

Gelsolin: A historical perspective

The importance of "gel" to "sol" transformation in cell motility was appreciated even before the existence of microfilaments were known (de Bruyn, 1947). It was established from microscopic studies that the cytoplasm (protoplasm) of large amoeboid organisms cold exist in a fluid, or a more solid gel-like phase, and that one could produce the other. The dynamic state of the cytosol is the basis for many important cellular processes, from cell locomotion, secretion, cytokinesis and synaptic plasticity.  It is now appreciated that these reversible gel to sol transformation results from the re-organisation of the actin based cytoskeleton. Actually, gel to sol transformation can be accomplished by a number of concomitant events, actin filaments are severed into small fragments that lowers the viscosity, and the actin filaments themselves de-polymerise, and a variety of crosslinking proteins are triggered to loosen their grip of the filaments.  All of the events are modulated or mediated by "actin-binding proteins", that occur in a number varieties.  Gelsolin is an actin binding protein that has many properties that makes it very likely to be primarily involved in all important gel to sol transformations, and has been given its name in recognition of this.  Gelsolin was first identified in macrophages (Yin & Stossel, 1979; 1980) and soon after in platelets (Wang & Bryan, 1981), and in serum (Harris et al, 1980). Gelsolin has also been known as brevin (Harris & Schwartz, 1981) and confusingly "actin depolymering factor" (Harris & Gooch, 1981;  Norberg et al, 1979), this name has also been given to another group of filament severing/depolymerising proteins of lower molecular weight (see ADF/Cofilins).

 
Gelsolin: Function and Structure
The domain structure of gelsolin.  There are three actin-binding sites (Bryan, 1988) spread across three domains. G1 and G4 Pope et al, 1996 ) bind G-actin, whereas G2 binds F-actin strongly and G-actin 100x less strongly ().  G2 also binds tropomyosin (Koepf & Burtnick 1992; Maciver et al, 2000).  The entire molecule is regulated by PIP2 binding at two sites in G1 and G2.
Click here for a diagram of the domain structure of the whole Gelsolin/Villin family.

Gelsolin is a comparatively large and complicated actin binding protein consisting of six-similar domains that have very different properties.  This complexity of form reflects a complexity of function.  Not only is gelsolin modulated by acidic phospholipids (see Gelsolin and Phospholipids), but it also modulate the metabolism of these lipids that in turn have regulatory effects as mitogenicity of the whole cell (Yin, 1988).  

The family of which gelsolin is a member, may be divided into two groups (Weeds & Maciver, 1993); class I, severing and capping proteins, and the Class II, capping proteins that do not sever. Class II also includes capping proteins that have little or no sequence similarity to the gelsolin group. The class I group consist of either six (gelsolin, villin) or three (severin, fragmin, adseverin/scinderin) (Ampe et al, 1987; Andr et al, 1988; Nakamura et al,1994) , homologous domains.  Class II capping proteins in the gelsolin group consist of three domains.  Given the domain structure of gelsolin, hypothesis have naturally been forwarded suggesting that the whole group arose by two major events.  First, a 15,000 proto-actin binding protein became triplicated to form some members such as severin, and this gene then was subsequently duplicated to form gelsolin.  It is additionally supposed that villin arose from gelsolin, by the addition of a "head piece" (Yin, 1988) endowing this group with bundling activity (Friederich et al, 1989; Finidori et al,1992).  The hypothetical 15,000 Da proto- ABP, has not yet been discovered in nature in as much as no protein of this size with recognisable sequence to the gelsolin fold has been found.  However, although the ADF/cofilin group share no recognisable sequence homology, they do share a remarkable similarity in tertiary structure (Hatanaka et al, 1996), and a related group of ABPs, the twinfilins (Goode et al, 1998), consisting of two ADF/cofilin motifs have been discovered, in support of the general duplication hypothesis.  Again in favour of the hypothesis is the finding that the triple-domain proteins severin and fragmin are abundant in slime moulds and it seemed at first that the hexuple forms were only found in metazoans, since then villin-like proteins with six domains have been reported in Dictyostelium (Hofman et al, 1993) and possibly primitive eukaryote, Entamoeba (Ebert, 1993; 2000) spoiling this attractively simple hypothesis. 

The Gelsolin family structural repeat.

The segmental structure of the gelsolin family is apparent not only from the primary structure (Way & Weeds, 1988; Finidori et al, 1992) but from the inter-segmental location of proteolysis site (Kwiatkowski et al, 1985; Bryan & Hwo, 1986; Kwiatkowski et al, 1989) by differential stability and solubility of recombinantly expressed domains (Way et al, 1989; 1990; Pope et al, 1994). Each domain is between 125 and 150 residues.  The 3D structure of gelsolin domain 1 (McLaughlin et al, 1994).

Gelsolin Segment 1

Gelsolin segment 1 (G1) is the best characterised of all segments of the gelsolin family.  It was originally described as an N-terminal 17kDa chymotryptic fragment (CT14N) (Yin et al, 1988) that retained some actin binding functions. G1 binds actin monomer in a calcium insensitive manner, although a calcium is "trapped" between G1 and actin. G1 with an additional 10 amino-acids from the start of G2 is sufficiently for a weak severing activity.  This activity is about 100 times less than the whole protein.

Gelsolin Segment 2

(G2) contains a second PIP2 binding domain, and an F-actin actin binding site. The actin side-binding domain also has actin filament capping activity (Sun et al, 1994). The actin binding site is between 150-173 (Sun et al, 1994). The solution structure of segment 2 of severin has been deduced (Schuchel et al, 1994).  G2 also binds tropomyosin (Maciver et al, 2000) in a Ca2+ and pH sensitive manner reminiscent of the interaction.

Gelsolin Segment 3

(G3) No known function other than that of a spacer.

Gelsolin Segment 4

Sequence comparisons reveals G4 to be most similar to G1 and this is borne out by a comparison of the domain structures (Burtnick et al, 1997). G4 also binds to G-actin in a similar manner as G1 (Pope et al, 1996 ).

Gelsolin Segment 5

Gelsolin Segment 6

 

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Actin Binding Activity of the Gelsolin Family

Monomeric Actin Binding.  In the presence of Ca2+, gelsolin binds two actin monomers (Yin & Stossel, 1980; Bryan & Kurth, 1984).

Filament Binding. In addition to the two monomeric actin binding sites discussed above, gelsolin binds actin filaments by a third actin binding site.  Actually, this third site binds very weakly to actin monomers, but does not compete with G1 or G4-6 for binding indicating that the F-binding site binds at a different site on actin (Pope et al, 1990).

Capping activity.  Gelsolin binds two actin monomers to form a nucleus for actin polymerization and caps the barbed end of actin filaments. Chemical crosslinking studies (Doi, 1992) indicate that gelsolin indeed binds two actins diagonally apposite monomers, rather than the two longitudinal monomers supporting this notion.  Both G-actin binding sites (in G1 and G4) bind the same domain on actin (Pope et al, 1990).

Severing activity.  Severing of actin filaments requires G1 plus 10 residues of G2 ().  The severing activity of this fragment is about 100 times less than the whole protein, however with the F-actin binding domain present in G2, G1-2 (Way et al, 1992), is fully activity.  Severing of actin filaments by gelsolin is inhibited by phalloidin

Nucleation of actin polymerization.  Actin polymerizes from actin monomers, to form microfilaments when several criteria are satisfied (Pollard & Cooper, 1995; Sheterline & Sparrow, 1994).  The monomeric actin concentration must exceed the "critical concentration" (~0.1mm for ATP-bound actin in the absence of actin binding proteins, and in the presence of 1mM magnesium and salts greater than 50mM). These conditions exist in most if not all eukaryotic, yet approximately 50% of the actin in cells is monomeric.  A variety of actin binding proteins (such as the thymosins, ADF/cofilin and profilin) are thought to be responsible for the sequestration of this monomeric actin pool by preventing polymerization.  This "extra" intracellular actin can be polymerised upon supply of nucleation sites at.  Gelsolin has been known for some time to bind the barbed end of actin filaments (Wilkin et al, 1983) and to nucleate the polymerization of actin (Tellam & Frieden 1982).

 

Gelsolin vs Villin

The main difference between gelsolin and villin is the additional actin binding domain at the COOH terminus of villin; the inaptly named "head piece".  The head piece is reponsible for villins bundling activity (Glenney & Weber, 1981; Friederich et al, 1989), and is strongly homologous with a region of dematin (band 4.9) an actin bundling protein (Rana et al, 1993), Dictyostelium "proto-villin" (Hofmann et al, 1993).  The villin head piece binds actin on sub-domain 1, since it competes for binding with ADF (Pope et al, 1993) (which is presumed to bind primarily to sub-domain 1 and the lower-rear surface of sub-domain 2, see ADF/cofilin).  The head piece however, is not the only difference between gelsolin and villin as the placement of villin head piece in the analogous place in gelsolin does not produce microvilli as villin does when transfected into cells lacking them, but instead disrupts stress fibres (Finidori et al, 1992; Friedrich et al, 1992).  

Tissue distribution of the Gelsolins

There would appear to be a conserved tendency for gelsolins to be encoded by a single gene and to encode both a cytoplasmic and a serum form. This is true of the single human gelsolin gene (Kwaiatkowski et al, 1986) encodes both cytoplasmic gelsolin variant and the secreted form, chromosome 9 (Kwiatkowski et al, 1988b &c) cand the rat gelsolin gene (Vouyioklis & Brophy, 1997).  Even in Drosophila a form is secreted into the haemolymph (Stella et al, 1994). Muscle tissue is the major source of serum gelsolin (Nodes et al, 1987; Kwiatkowski et al, 1988a).  

Cellular localisation of the Gelsolins.

Gelsolin has been reported to be localized generally to actin rich structures (Yin et al, 1981) while others have concluded that gelsolin is diffusely distributed in platelets, white blood cells (Chaponnier et al, 1985) and cultured lymphoid cells (Thorstensson et al, 1982).  Ovary (Teubner et al, 1993 & 1994). Gelsolin has been localised in regions of cell-substratum contact or attachment in Rous sarcoma virus-transformed rat cells (Wang et al, 1984).  However, immunolocalization of gelsolin has been hampered by the fact that gelsolin is present at high concentration (0.2mgs/ml) (Kwiatkowski et al, 1988b) in vertebrate serum, contaminating many reagents used in immunolocalization studies.  Many studies have therefore erroneously concluded that gelsolin is localized along filaments in permeablized cells of a variety of types (Carron et al, 1986).  With this caveat in mind, more recent work has concluded that gelsolin is localized at the cell periphery in platelets (Carron et al, 1986).  Other studies since the report of Carron and coworker's work, designed to eliminate the risk of xenogenic gelsolin still insist that gelsolin is located along stress fibres in fibroblasts (Kanno & Sasaki, 1989; Dissman & Hinssen, 1994) and in the I-Z-I region in muscle cells (Dissman & Hinssen, 1994).  Immunogold ultra-structural electron microscopy (Hartwig et al, 1989), has revealed that gelsolin is associated with actin filaments and cell membranes of macrophages and platelets, presumably in association with polyphosphoinositides.  In neuronal cells gelsolin has been localized to the growth cone (Tanaka et al, 1993) and to the (Tanaka & Sobue,1994)

The location of other members of the gelsolin family have been less controversially determined.  Severin has been found to be concentrated at the leading edge of Dictyostelium amoebae (Brock & Pardee, 1985).  Adseverin/scinderin become localised to the cortex of secretory cells where they apparently remove actin around the vesicles to allow them to dock and fuse with the plasma-membrane (see Adseverin/Scinderin). Gcap is present in both the cytoplasm and the nucleus (Onoda & Yin, 1993; Prendergast & Ziff, 1991). Nuclear targeting of the protein is apparently stimulated by serine-threonine phosphorylation (Onoda & Yin, 1993).  Villin has also been localised to the microvillus in a number of studies (Matsudaira, 1992). Fragmin has been localised within the plasmodium of Physarum (Osborn et al, 1983; T'Jampens et al, 1997)

Gelsolins and Cytokinesis?  Many ABPs are known to be concentrated with actin in the cleavage furrow at cytokinesis and since the furrow depolymerizes as it contracts and gelsolins are proteins that depolymerize actin filaments it may be expected that gelsolin is a component of the cleavage furrow.  However, evidence for this has been slow n coming forward.  In contrast cofilin (another actin depolymerising protein) is known to concentrate in the furrow.  

Post Translational Modification of Gelsolins.

Phosphorylation  Gelsolin itself is not thought to be phosphorylated under "normal" conditions (Wang et al, 1984; Onoda & Yin, 1993), however it has been reported to be phosphorylated  by PP60c-src in the presence of PIP2 (De Corte et al, 1997). 

 

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Gelsolins and cancer

Gelsolin levels have often been discovered to be lowered in oncogenic transformations (Vandekerckhove et al, 1990; Asch et al, 1996)  A mutation in gelsolin is responsible for the transformation.  The mechanism by which gelsolin is down-regulated may be through epigenetic changes in chromatin structure through histone acetylation (Mielnicki et al, 1999). The role (if any) between oncogenic transformation and gelsolin may be connected to the role that gelsolin seems to have in apoptosis (see below).  Villin is used as a marker for bowel ( ) and kidney cancers (Grone et al, 1986).

 
Gelsolins in other diseases

FAF, Lewy bodies,
Gelsolin and Cystic Fibrosis
Gelsolin Related Proteins
Adeseverin/Scinderin

Although Adseverin (also known as scinderin) appears to be a smaller protein on SDS-PAGE than gelsolin, it shares the same overall domain structure and is approximately the same size.  Adseverin is expressed in a wide variety of tissues and is especially abundant in brain.  It appears to have a specific role in regulated secretion.  (See Adeseverin/Scinderin pages).

 

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Flightless-I

The flightless-I gene is required for cellularisation in the early embryo of Drosophila melanogaster (Campbell et al, 1993).  

 
Gelsolin as a tool

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