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A Brief History of the Coronin Family

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Author Information and Affiliations

The Coronin Family of Proteins, edited by Christoph S. Clemen, Ludwig Eichinger and Vasily Rybakin.
Read this chapter in the Madame Curie Bioscience Database here.

What I'd like to do in this chapter is to share with you my recollections from the earliest days of coronin research and then to provide an overview of the still-developing story of this fascinating family of proteins.

Oktoberfest Beats Falling-Ball Viscometry

In the fall of 1989 I arrived as a postdoc in Guenther Gerisch's department at the Max Planck Institute for Biochemistry in Munich to start a project on actin-binding proteins from Dictyostelium discoideum. Angelika Noegel (University of Cologne) and Michael Schleicher (University of Munich) had at the time their own subgroups in the Gerisch department that had done some beautiful work in this area.1 Schleicher's approach had been to purify proteins that affected actin polymerization, primarily using falling-ball viscometry and pyrene-actin fluorimetry as assays. Noegel had led the molecular biology aspects of the projects, which involved the cloning of the genes and their inactivation by gene disruption followed by the analysis of the mutants.

When I arrived in the lab, however, I found some general frustration with the fact that some of the proteins that had been purified based on dramatic effects on in vitro actin polymerization (e.g. severin) were at least partially redundant in Dictyostelium.1-4 Thus, the loss of the proteins did not have much of an effect on the cells and did not generate a phenotype that could shed some light on the biological function of the proteins.

Another thing I found out very quickly was that there were no unclaimed actin-binding proteins in the department that I could get to work on right away and that I'd have to decide quickly on a way of finding my own. I didn't have the temperament of a biochemist and I wasn't too keen on the Schleicher approach which might require spending much of my precious time in Munich (especially during Oktoberfest) timing little steel balls falling through tubes filled with F-actin. I wasn't too enthusiastic either about the Gerisch proposal to raise monoclonal antibodies against a crude detergent-extracted cytoskeletal fraction and to screen them for interesting cytoskeletal localization by immunofluorescence. I wasn't entirely against this “get antibodies first and ask questions later” approach and I certainly wanted to learn how to make monoclonal antibodies (for which the Gerisch group was well known), but I just thought that raising mAbs against crude cytoskeletal fraction was too much of a shot in the dark. I thought a more specific, cleaner cytoskeletal fraction would be better and after some digging in the literature I came across a cytoskeletal preparation called the “contracted pellet” that had been used previously5 to purify a number of cytoskeletal proteins. This protocol involved the preparation of a highly concentrated cytoplasmic fraction from which acto-myosin could be precipitated, along with associated proteins.

My version of the preparation was similar to those described previously and consisted mostly of actin and myosin (heavy chain plus two light chains), a previously characterized 30 kD actin cross-linker5 and two bands of 17 kD and 55 kD, respectively. Nothing was known about the latter two proteins but hoping that they would be cytoskeletal I carried on with their characterization. I purified the two proteins further from the contracted pellet fraction and right away used them to immunize mice and to get some peptide sequence. It was not long before we had plenty of hybridomas producing antibodies against the proteins and enough peptide sequence to suggest that the proteins were novel. The immunofluorescence images we obtained with the antibodies gave us the first indication that we had stumbled across something interesting. Anti-p55 gave stunning images of actin-rich structures in the cells including crown-shaped protrusions on the surface of the cells, for which I decided to name the protein (corona is Latin for crown). The antibodies against p17 gave an interesting but less glamorous labeling pattern, showing general enrichment throughout the cell cortex.6 The 17 kD protein was named coactosin and is a member of the ADF/cofilin family with an interesting story of its own.7

We were all excited about the labeling pattern that anti-p55 gave but given all the previous work in the department on other cytoskeletal proteins that was based on a biochemical activity, there was some skepticism about this arriviste protein. Initially, I couldn't even show much binding to actin, the interaction being very sensitive to the concentration of NaCl. Fortunately, around that time I had a chance to talk to Ron Vale (University of California, San Francisco) on the long drive to a meeting in Austria. Vale, who had first characterized kinesins, suggested that I should try K-glutamate instead of NaCl, since K+ and glutamate were more representative of the intracellular milieu than were Na+ and Cl-. This did the trick and I was able to show binding of coronin to F-actin, but found no obvious effect on the polymerization of G-actin or an effect such as severing or cross-linking of F-actin. I think this finding was the source of some Schadenfeude among the falling-ball crowd in the department but I didn't know any better than to remain optimistic and, fortunately, molecular biology soon made the coronin story a lot more interesting.

Using the excellent mAbs that we had made I was able to quickly clone coronin cDNAs from an expression library. To my chagrin vis-à-vis the biochemists, it didn't look like any actin-binding protein that had been sequenced before. Intriguingly it had homology to, of all things, the β subunits of the trimeric G-proteins (Gβ). We found five repeats of the WD motif that was characteristic of the Gβ subunits, in which it was repeated seven times. This similarity was puzzling but full of intriguing possibilities. The homology to Gβ led to some wild speculation that perhaps coronin was a link between the actin cytoskeleton and the G protein-coupled cAMP receptor that triggered chemotaxis in Dictyostelium. Buoyed by these ideas, but in the absence of any biochemical evidence to support the hypothesis, we sent the manuscript describing the initial characterization of coronin to Nature, which, rightly so, rejected the paper for not being substantial enough.

A more subdued manuscript was eventually published8 but for more substance I turned to molecular biology, with which I was most comfortable. With a cDNA in one hand and a recent paper9 describing a new, faster and more efficient method for gene disruption in the other, I quickly set about the job of finding out what coronin did in the cell. The transfection worked like a charm and within a week the technician working with me reported some strange looking cells in our plates: monstrous cells several times the size of normal cells and containing many nuclei. Knocking genes out in Dictyostelium was then still something of an event and we were sitting on top of the world when we confirmed the gene disruption and the absence of coronin with our antibodies.

In our characterization of the mutant we focused on chemotaxis and cytokinesis.10 Using image analysis software developed in the department we found that the mutants migrated and oriented properly in cAMP gradients but moved less effectively. I was more intrigued by the cytokinesis defect, manifested by a very photogenic phenotype. In studying this defect we found that unlike myosin II mutants, the coronin mutants were not as severely impaired in performing cytokinesis,9,11 they just didn't seem to be able to do so as effectively as normal cells. Interestingly, the coronin mutants grew fairly well in liquid, while the myosin mutants lysed after a few rounds of mitosis without cytokinesis. We interpreted this to mean that while coronin might have a role in the cleavage furrow, part of the effect on cytokinesis was due to the role played in the process by cell locomotion (and hence daughter cell separation), which was clearly affected in the mutants.10,12

The defect in locomotion and cytokinesis left little doubt that coronin was playing an important role in the actin cytoskeleton but the phenotype did not give a clear indication of what coronin was doing. There was an intriguing subtlety to the phenotype, in that the cells were quite viable and seemed to be able to do everything wild-type cells could do, just not as quickly or effectively. Coronin appeared to play a non-essential but significant accessory role in a variety of actin-based processes. In addition, the presence of the WD repeats gave us a reason and, lacking a biochemical activity, an excuse to speculate that whatever coronin did to actin happened through the interaction with other proteins. Putting these ideas together, the best we could say for a long time and with a lot of hand waving, was that coronin was affecting “cytoskeletal reorganization” and “actin dynamics” in partnership with other proteins (Fig. 1A).10

Figure 1. Models of coronin function.

Figure 1

Models of coronin function. A) Speculative model of coronin function (1995, E. L. de Hostos, unpublished) suggesting the involvement of coronin in actin dynamics in partnership with other actin-binding proteins. B) Current model of core coronin functions. (more...)

Coronin Becomes a Real Protein

Despite the remarkable phenotype caused by the loss of coronin, the lack of a biochemical explanation or evidence for homologous proteins in other organisms resulted in coronin being regarded as just an intriguing curiosity from slime molds when I left Munich in 1992. Within a couple of years, however, work by a number of labs would start making it a bona fide member of the cytoskeletal world.

Markus Maniak (University of Kassel), who had earlier done his PhD under Wolfgang Nellen in the Gerisch department, returned to Munich and quickly made good use of a fabulous new tool known as green fluorescent protein (GFP) to tag coronin and follow its dynamic localization in vivo.13,14 This was the first reported fusion of GFP to a component of the actin cytoskeleton and the beautiful movies provided insight into the role of coronin as well as demonstrating the huge potential of GFP for tracking dynamic processes in cells. The movies showed clearly the involvement of coronin with the actin network at the leading edge of migrating cells, in the cortical crowns and with the actin coat that forms around phagocytic cups and which is likely to be a driving force in their formation. GFP-coronin showed that within minutes of their formation, phagosomes shed their coat containing actin and coronin and that coronin relocalizes to the cell cortex.

In parallel with the GFP-coronin studies, the Gerisch group made an intriguing observation about the coronin knockout mutants. They found that these cells had an abnormally broad cell cortex and more F-actin than wild-type cells.14 Furthermore, they showed that treatment with the barbed-end capping agent cytochalasin A could restore the cortex to a more normal configuration. In light of these results they interpreted the cell architecture and sluggishness of coronin mutants in terms of a role for coronin in promoting the disassembly of actin filaments.

The publication of the Maniak's beautiful coronin-GFP results was followed by the identifcation of the first coronin homolog,15 a 57 kD protein from human and bovine immune tissues (coronin 1A, also known as coronin 1 and p57). In their characterization the authors also recognized that coronin had a coiled-coiled domain at the C-terminus, a feature that we had missed in our description of the Dictyostelium coronin and which has turned out to be almost universal in the coronin family and essential for oligomerization and some of its key interactions.16-20 Finding coronin in mammals had a large impact on how this protein was perceived and allowed it to start shedding its status as a Dictyostelium curiosity. As it turns out, the discovery of coronin 1A in immune cells was just the beginning of one of the most interesting coronin stories.

Like Dictyostelium coronin, coronin 1A was found to be involved in phagocytosis. The protein was found to copurify with components of the NADPH oxidase (phox) complex, which assembles on the surface of phagosomes to generate superoxide aimed at killing pathogens caught inside.21 Much like in Dictyostelium, phagosomes in immune cells such as neutrophils have a transient coat containing actin and coronin. Work on the mechanism by which mycobacteria survive phagocytosis by macrophages has also led to coronin 1A. Jean Pieters (University of Basel Biozentrum) and coworkers discovered that unlike phagosomes with heat-killed mycobacteria, phagosomes with viable mycobacteria retained the coat of actin and coronin 1A (TACO).22 We will discuss this in more detail in a section below.

Core Function

Within a couple of years of the discovery of coronin 1A, similar proteins had been found in a variety of model organisms and additional coronins had been identified in mammals, including two close relatives of coronin 1A, coronin 1B and coronin 1C (the three have also been referred to in the literature as coronins 1, 2 and 3, respectively).23-27 The ubiquity of coronins and, for some at least, an evolutionarily conserved role in the medically relevant process of phagocytosis brought coronins into the mainstream but did not clarify their function.

Since the coronin-null mutants of Dictyostelium moved and divided inefficiently and lacked the characteristic F-actin-rich crowns on their surface, I initially envisioned coronin as being involved in somehow enhancing actin polymerization or stabilizing actin filaments. As mentioned earlier, however, Gerisch and coworkers later came to an opposite, more educated hypothesis, one with a role for coronin in promoting the disassembly of actin-filaments and “balancing the activities of proteins that nucleate actin polymerization”.14 Gerisch was on to something but biochemical evidence would have to wait until the discovery of Crn1p and the Arp2/3 complex.

Coronin from budding yeast, Crn1p, was initially identified by an in silico homology search28 and in parallel purified, surprisingly, by microtubule affinity chromatography29. Microtubule binding not withstanding, Crn1 turned out to be true to its other coronin relatives and shown to be intimately involved with the actin cytoskeleton. Bruce Goode (Brandeis University), then a postdoc with Georjana Barnes and David Drubin at Berkeley, showed for the first time evidence for a biochemical function: the stimulation of polymerization of pure actin and the bundling of actin filaments (as well as the cross-linking of these actin bundles to microtubules).29 These properties, however, have turned out to be only a short preview on the functions of coronins in regulating actin dynamics.

For many years the actin cytoskeleton had been understood mostly in terms of a rather limited set of components and functions: actin (G and F), capping proteins, cross-linkers, severing proteins and, of course, myosin. But that construction set gained a whole new dimension with the discovery and initial characterization of the Arp2/3 complex.30-32 Nucleation is the rate-limiting step in actin polymerization and therefore the generation of nucleation sites is a key regulatory step in the assembly of actin networks. Until the discovery of the Arp2/3 complex, the severing of actin filaments by proteins such as cofilin was thought to be the primary mechanism for generating nucleation sites and stimulating polymerization. Arp2/3 is a complex of seven proteins that drives the rapid de novo assembly of F-actin, by nucleating daughter filaments from the side of existing filaments and forming a branching meshwork.33,34 Intriguingly, it was found that preparations of Arp2/3 from human neutrophils contained sub-stoichiometric amounts of coronin 1 A, in addition to the seven subunits of the complex.35 The presence of coronin in preparations of the Arp2/3 complex suggested, finally, a partnership through which coronin might be affecting “actin dynamics”.

Bruce Goode and coworkers started to reveal the nature of this partnership when they found that Crn1p bound Arp2/3 via its coiled-coil and recruited it to the sides of pre-existing F-actin filaments. In the absence of pre-existing filaments they found, however, that Crn1p inhibited the actin-nucleating activity of the complex. Therefore, they proposed that coronin inhibits Arp2/3-mediated polymerization in the cytoplasm, but promotes nucleation and branching at the cell cortex.17

The prevalence and importance of the coronin-Arp2/3 partnership has been validated further by a number of studies.36-39 Working with coronin 1B, James Bear's group (University of North Carolina) has shown that phosphorylation by protein kinase C (PKC) of a widely conserved serine residue (S2) inhibits the interaction of coronin with Arp2/3.37 S2 phosphorylation has also been shown to control Arp2/3 interaction in coronin 1A.40 Bear's group found that cells expressing coronin 1B with a phosphomimetic aspartate substitution (S2D) were sluggish and displayed reduced ruffling, as might be expected from a knockout.37 Indeed, Rat2 cells depleted of coronin 1B by shRNA expression showed a consistent phenotype.39 A key finding in this study was that retrograde flow of actin filaments from the cell periphery was drastically reduced. While the details as to exactly how the coronin-Arp2/3 partnership works are still being worked out, this observation illustrates clearly that one of its key functions is to regulate filament turnover.

Polymerization and depolymerization are two sides of the same coin (or filament, in this case), so what about the role of coronin in filament disassembly? Goode and coworkers had shown that while the deletion of Crn1p caused no overt phenotypes, it did cause a more severe synthetic phenotype when combined with alleles of cofilin (cof1-22) and actin (act1-159), which were known to reduce actin filament turn-over and stabilize F-actin in vivo.29 The synthetic phenotypes observed would make sense if coronin had a role in depolymerization and its loss made things worse for the cells by reducing filament turnover even further. This interpretation was supported by evidence suggesting that in vitro Crn1p in fact synergizes with cofilin to promote filament disassembly (M. Gandhi and B. Goode, personal communication). Results consistent with this observation have come from the study of actin dynamics in the comet tails generated by Listeria.

A study aimed at purifying factors that would stimulate the otherwise weak in vitro activity of cofilin to depolymerize the actin tails identified two proteins, coronin 1A and the actin-binding protein Aip1 that can do so, separately and in combination.41 The authors suggested that coronin stimulates cofilin activity indirectly, by binding to actin filaments and altering their structure in a way that facilitates the binding of cofilin.41 Work on coronin 1C36 showing that antibodies directed against coronin will co-immunoprecipitate cofilin, however, has suggested a direct interaction with cofilin as well. More recent work from the Bear lab, however, found no evidence for enhanced binding of cofilin to F-actin in the presence of coronin 1A or 1B.38 Instead they found that coronin binding actually protected the actin filaments from cofilin-induced depolymerization.38 They have proposed that coronin 1B can enhance cofilin activity in vivo by directing the localization of the slingshot phosphatase (SSH1L) to lamellipodia, where it can activate cofilin by dephosphorylation.39

The picture of how coronins regulate actin filament turnover is complicated and not yet complete, but it is clear that it is involved at both ends, so to speak, in filament assembly and filament disassembly (Fig. 1B). I think that one of the surprises in the picture that is emerging is that F-actin itself is one of coronin's key partners. In other words, rather than being just a substrate, as it is for other actin-binding proteins, F-actin seems to be an active partner that regulates coronin function. Not only does it appear that coronin can sense the presence or absence of F-actin and regulate Arp2/3 accordingly,17 there is evidence that coronin can also distinguish the nucleotide state of the F-actin involved. Bear's group has shown38 that coronin 1B has much higher affinity for ATP-F-actin than for ADP-F-actin, an observation that implies that coronin can determine whether it is at the ATP-actin-containing barbed end of filaments or the ADP-actin-containing pointed end. It remains a major future challenge to put together a model that harmonizes all of the biochemical results with all of the phenotypic observations, but I think that we are starting to see a sophisticated coronin-based system for fine-tuning actin turnover in response to temporal and spatial cues. In Chapter III-1 Bruce Goode will delve into this topic further.

All in the Family

One recurring question about the coronin family is how conserved are the interactions of coronins with actin? Even though our knowledge of the family is far from comprehensive, I think that it is fair to say that interacting with actin is ancestral to the family and that actin-regulatory functions are likely to have evolved early and been retained by many members of the family.16,26,42 That said, I think there is likely to be significant diversity in the details of their actin-regulatory functions, both in terms of inputs (i.e., signals and partners) and in terms of outputs (i.e., targets). This diversity may support the specialization of different coronins for a wide range of actin-based processes (e.g., cell migration vs phagocytosis) in different cell types or even in the economy of the same cell. Some coronins appear to have evolved out of their actin-regulatory functions completely but I suspect that if we look hard enough we will always find actin in their circle of protein partners. In considering coronin diversity, I like to visualize coronin functions in terms of a model like the structure of the earth, with ancestral functions at the core and accessory functions in layers more or less removed from the core functions (Fig. 2).

Figure 2. Range of coronin activities.

Figure 2

Range of coronin activities. The activities of the coronins range from the ancestral core functions mediated by actin binding and affecting actin turnover to accessory functions such as microtubule (MT) and membrane binding. Additional functions may include (more...)

The coronin family shows its greatest diversity in mammals, in which it can be divided into three types.16 Type I includes coronins 1A, 1B and 1C [and coronin 6; for latest knowledge on coronin phylogeny see chapter II-2], which like Crn1p from yeast, have been shown to be involved in the regulation of actin dynamics through Arp2/3 and cofilin (core functions) and thus belong in the same functional group. Dictyostelium coronin is almost certainly another member of this group, but this has not been proven biochemically.

Coronin 1A is expressed preferentially in immune tissues along with coronin 1B and 1C which are expressed ubiquitously.16,26 With one possible exception, the reports describing the phenotype of cells in which these coronins have been eliminated or inhibited are similar and consistent with the phenotype of the original Dictyostelium knockout mutants. The thymocytes from knockout mice lacking coronin 1A are impaired in chemotaxis and locomotion in general40 and, interestingly, they tend to undergo apoptosis in vivo. This apoptotic phenotype is thought to be a consequence of excess of F-actin disrupting mitochondrial integrity.40,43 In human neutrophils, coronin 1A lacking the coiled-coil domain has a dominant-negative effect and disrupts phagocytosis, chemotaxis, spreading and adhesion.19,20 Surprisingly, however, the truncated coronin has no effect on the secretion or the activation of the phox complex, with which coronin is thought to associate. Rat2 cells in which coronin 1B had been depleted by shRNA also show impaired motility.38 Work on coronin 1C using dominant negative mutants and siRNA has shown results similar to those seen with coronins 1A and 1B, as well as an effect on cytokinesis.36

The one exception to this consistent spectrum of phenotypes comes from studies of another lineage of knockout mice lacking coronin 1A.44 Surprisingly, the study concluded that coronin 1A was dispensable for actin-mediated processes such as motility. This is an intriguing observation but I suspect that it is an issue of penetrance rather than a fundamental discrepancy with the results obtained by other groups. More importantly, however, this study confirmed the hypothesis mentioned earlier that coronin 1A is required for mycobacteria to survive in the phagosomes of infected macrophages.22 Initially it was speculated that the retention of actin and coronin around phagosomes might prevent the fusion with lysosomes, thus protecting the mycobacteria from destruction. Work with cells from the knockout mice has shown, however, that the role of coronin 1A in this process goes beyond the cytoskeletal realm. Retention of coronin 1A leads to the Ca2+-dependent activation of calcineurin (protein phosphatase 3), which in turn prevents the fusion of lysosomes with the phagosome.44 In the context of phagocytosis then coronin 1A seems to have acquired a slew of accessory functions beyond its core functions. These include actin-independent binding to the cholesterol-rich phagosome membrane (through the WD domain),45 binding to the phox complex,21 an undefined role in the release of Ca2 required for calcineurin activation.44 Jean Pieters will discuss this remarkable story in more detail in Chapter IV-1.

While the results concerning Type I coronins are painting a mostly consistent story about their role in actin dynamics, much less is know about those classified as Type II (coronin 2A and 2B) and Type III (coronin 7).16 As we learn more about them they are likely to provide additional examples of functionality distant or completely divorced from the core functions, Coronin 2B (ClipinC) from brain has been shown to bind F-actin and the actin and membrane-binding protein vinculin, but it is not really known what role it plays in the neuronal cytoskeleton.46 Coronin 2A may be up to something far removed from its ancestral functions and has been implicated in transcriptional regulation, due to its presence in the nuclear receptor corepressor (N-CoR).47 A role in transcription may seem “way out there” in the outer reaches of coronin space, but curiously, the only protein detected (other than coronin itself ) in a two-hybrid screen using full-length Dictyostelium coronin as a bait was a protein (DB10 or coronin binding protein; XP_643969) that showed a sharp nuclear localization when tagged with GFP (D. Benhayon, W. Gu and E. L. de Hostos unpublished).

Type III coronins are different from other coronins in that they consist of two coronins fused in tandem but lacking coiled-coiled domains. In humans, they are represented by coronin 7. Type III coronins from Caenorhabditis (POD-1)48 and Drosophila (Dpod1)49 have been shown to be involved with actin but seem participate in different processes. The embryonic-lethal phenotype of POD-1 mutants suggests that it is required for polarized membrane trafficking necessary for the establishment of anterior-posterior polarity in the embryo.42,48 Consistent with this phenotype, coronin 7 is associated with the Golgi apparatus and has been implicated in vesicle trafficking42,50,51 (see also chapter III-4 by Rybakin). So far coronin 7 has not been found to interact with actin but I am holding out for the possibility that future research will show it to be the exception that proves the rule that all coronins interact with actin.

Drosophila Dpod1 does not seem to participate in membrane trafficking like POD-1 but it can bind microtubules, a function that coronins seem to have acquired more than once. Crn1p and Dpod1 both have a microtubule-binding domain with homology to MAP1B that lets them crosslink microtubules to actin-filaments.48,49

Full of Surprises

WD repeats were, in a way, where the coronin story started and so I can't end this review without a word about the structure of coronins. The archetypal WD repeat proteins are the Gβ subunits, which have seven repeats and fold into a seven-bladed β-propeller.52,53 Although motif searches only identify five canonical WD repeats in coronins, the crystal structure of coronin 1A has shown that there are two cryptic WD repeats and that like the Gβ subunits, the protein folds into a seven-bladed β-propeller structure.54 So while coronin did not turn out to be a direct link between G-protein coupled receptors and the cytoskeleton, they have turned out to be more structurally similar to the Gβ subunits than was originally thought based on sequence homology.

The WD repeat domain has been shown to be involved in a number of important interactions: binding actin filaments36,38 (although the coiled-coil can too),17 phosphorylation by protein kinase C (PKC)37 and actin-independent binding of membranes.45 The perception of the WD repeat domain as a nexus of protein-protein interactions has not been substantiated, but that may still happen, as more interactions (e.g., Golgi, Ca2+ release, SSH1L) are mapped on the protein structure. It is clear, however, that even though the WD domain with its β-propeller structure wins the crystallographic beauty contest, the humble coiled-coil domain is not just a “structural” element and is responsible for some key interactions such as binding actin and the Arp2/3 complex.17 Coronins are, indeed, full of surprises.

Looking back over 16 years of work on coronins, what strikes me the most is how close, yet how very far away we were in the beginning to understanding the function of this interesting family of proteins. From the time we first got a look at the Dictyostelium coronin sequence and saw the WD repeats we guessed that the protein was likely to interact and perform its function through multiple binding partners. Later, based on the phenotype of the Dictyostelium mutants, we went on guessing and suggested that coronin had something to do with actin dynamics. Yet it has taken years of intricate work and the discovery of new proteins to substantiate this and come to a fair understanding of how coronins perform their core functions.

For someone who planted a small seed years ago and has watched others cultivate it, it is satisfying to see how the coronin story has grown and different strands of evidence have started to come together so neatly. Most rewarding is the fact that coronin is turning out to be an important player in the key process of actin turnover. But not all is said and done and as in any good family saga, I think that this story has a long way to go and this quirky family will continue to reward researchers with unexpected results and new insights into fundamental cellular processes.

Acknowledgement

The author would like to thank Bruce Goode, Jim Bear and Angela Barth for helpful discussions, and Chris Franklin for help with Figure 2.

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