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Gelsolin and Related Proteins in Vertebrate Model Organisms

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Gelsolin and Related Proteins in Vertebrate Model Organisms e-ISSN 1734-9168 Folia Biologica (Kraków), vol. 67 (2019), No 4 http://www.isez.pan.krakow.pl/en/folia-biologica.html https://doi.org/10.3409/fb_67-4.16 Gelsolin and Related Proteins in Vertebrate Model Organisms Marta MIGOCKA-PATRZA£EK , Joanna NIEDBALSKA-TARNOWSKA , Arnold GARBIEC , Magda DUBIÑSKA-MAGIERA , and Ma³gorzata DACZEWSKA Accepted December 17, 2019 Published online December 30, 2019 Issue online December 31, 2019 Review MIGOCKA-PATRZA£EK M., NIEDBALSKA-TARNOWSKA J., GARBIEC A., DUBIÑSKA-MAGIERA M., DACZEWSKA M. 2019. Gelsolin and related proteins in vertebrate model organisms. Folia Biologica (Kraków) 67: 159-167. Gelsolin, encoded by the Gsn gene, is a highly conserved actin-binding protein detected in all studied eukaryotic organisms. Gelsolin is the founding member of the gelsolin superfamily of proteins, whose main functions are binding, severing, and capping actin filaments. Moreover, gelsolin is engaged in apoptosis regulation, signal transduction, and embryonic development. Gelsolin is also implicated in some human diseases such as Alzheimer disease and familial amyloidosis of the Finnish type (FAF). Because of its multifunctionality, gelsolin is a potential candidate for diverse therapeutic applications. Most of our knowledge about gelsolin superfamily proteins comes from investigations conducted on vertebrate model organisms such as zebrafish (Danio rerio), African clawed frogs (Xenopus laevis), chickens (Gallus gallus), and mice (Mus musculus). Here, we present fundamental findings as well as new knowledge to indicate main research directions and future possibilities. Different model organisms provide specific possibilities and present particular advantages. However, all of them give useful data, which allow us to gain a better understanding of the function of gelsolin and related proteins. Key words: gelsolin, adseverin, CapG, flightless I, advillin, villin, villin-like, supervillin, apoptosis. * Marta MIGOCKA-PATRZA£EK , Joanna NIEDBALSKA-TARNOWSKA, Arnold GARBIEC, Magda DUBIÑSKA-MAGIERA, Ma³gorzata DACZEWSKA, Department of Animal Developmental Biology, Institute of Experimental Biology, University of Wroc³aw, Sienkiewicza 21, 50-335 Wroc³aw, Poland. E-mail: [email protected] Joanna NIEDBALSKA-TARNOWSKA, Laboratory of Molecular and Cellular Immunology Department of Tumor Immunology Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroc³aw, Poland. Gelsolin, a protein of 82-84 kDa, is an actin-bind- acids called a linker sequence (Fig. 1) (KWIATKOWSKI ing protein regulated by calcium (SILACCI et al. et al. 1986, 1988, 1989; BOLLATI et al. 2019). It 2004). In mammals, gelsolin superfamily proteins was proposed that the six gelsolin subunits comprise gelsolin, adseverin, CapG, flightless I, (S1–S6) evolved from a single domain prototype advillin, villin, villin-like and supervillin (LI et al. through gene triplication, followed by a duplica- 2012; NAG et al. 2013; SHEKHAR et al. 2016). This tion event (WAY &WEEDS 1988). In mammals, conserved protein superfamily, widely expressed differences between gelsolin isoforms arise from in eukaryotic cells, exists as cytoplasmic, the presence of a disulfide bond between Cys188 plasma/secreted and brain isoforms. In mammals, and Cys201 in plasma gelsolin, and 11 additional gelsolin is encoded by a single gene and expressed amino acid residues on the N-terminal domain in through alternative splicing. The basic functions brain gelsolin. Furthermore, contrary to cytoplas- of gelsolin are binding, severing, and capping ac- mic gelsolin, the plasma isoform contains a signal tin filaments (SUN et al. 1999; FELDT et al. 2018). peptide and 23-25 amino acid residues more on the A common sequence of all isoforms contains N-terminal domain (BUCKI et al. 2008). 730 amino acids. Gelsolin has six subunits (S1-S6), It has been shown that gelsolin has three different organized into two domains: on the N- (S1-S3) and actin binding regions: a calcium-independent mono- C-terminal (S4-S6) halves, linked through 70 amino mer binding fragment (S1), a calcium-independent Ó Institute of Systematics and Evolution of Animals, PAS, Kraków, 2019 Open Access article distributed under the terms of the Creative Commons Attribution License (CC-BY) OPEN Ð ACCESS http://creativecommons.org/licences/by/4.0 160 M. MIGOCKA-PATRZA£EK et al. Fig. 1. Cross-species comparison of the gelsolin protein structure. The upper part of the figure shows a comparison of the gelsolin protein’s architecture in various organisms: human (Homo sapiens), mouse (Mus musculus), chicken (Gallus gallus), African clawed frog (Xenopus laevis), and zebrafish (Danio rerio). Conserved functional domains and binding sites are highlighted by different color boxes. The proportions between individual sequences of proteins, domains, and binding sites have been preserved. On the lower part of the figure, a phylogenetic tree based on a protein sequence comparison of the gelsolin family from the various organisms is shown. Sequence alignment and phylogenetic tree: ClustalW2, www.ebi.ac.uk. filament binding fragment (S2-3), and a calcium- part in cytoskeleton structure reorganization, and dependent monomer binding fragment (S4-6) influences cell shape changes and cell movement. (BRYAN 1988). Besides Ca2+ promoting gelsolin The main function of plasma gelsolin, is participa- activity, intracellular pH, phosphoinositides, and tion in the removal of G-actin and F-actin from the tyrosine phosphorylation affect gelsolin regula- bloodstream after cell damage. It is noteworthy tion (SILACCI et al. 2004). Gelsolin also binds to that actin in the extracellular environment has phosphatidylinositol 4,5-bisphosphate (PIP2). toxic effects (LI et al. 2012). The third isoform, PIP2 inhibits the actin filament, severing activity brain gelsolin, is involved in myelin sheath forma- of a proteolytic fragment of gelsolin encompass- tion and central nervous system development ing its N-terminal half (JANMEY &STOSSEL (VOUYIOUKLIS &BROPHY 1997; MAZUR et al. 1987). 2016). The gelsolin cytoplasmic and plasma isoforms In gelsolin, the substitution of Asp187Asn or are produced by skeletal, smooth, and cardiac Asp187Tyr causes familial amyloidosis of the Fin- muscles, whereas the brain isoform is observed in nish type (FAF), a rare hereditary amyloid poly- oligodendrocytes, lungs, and testis. Differences in neuropathy characterized by corneal lattice the structure of individual isoforms also modulate dystrophy, progressive cranial, and peripheral their functions. Cytoplasmic gelsolin is responsi- neuropathy, and skin changes (SOLOMON et al. ble for the regulation of cell actin dynamics, takes 2012). Gelsolin could be potentially used for the Gelsolin in Vertebrate Model Organisms 161 treatment of Alzheimer’s disease, caused by the larly sized exons (JIA et al. 2009). Like scinla, accumulation and deposition of amyloid beta in scinlb is expressed in the adult cornea, although at the brain. Plasma and cytoplasmic gelsolin have lower levels than scinla (JIA et al. 2007). Both the ability to connect with amyloid beta, thus limit- scinla and scinlb belong to a distinct branch that ing the aggregation of this protein (ISAACSON et al. clusters with, but is separate from, the scinderin 1999; HUFF et al. 2003; ANTEQUERA et al. 2009; vertebrate cluster. Thus, scinla and scinlb are ZORGATI et al. 2019). fish-specific paralogs of scinderin (JIA et al. In our review, we focused on the role of gelsolin 2009). Scinla, scinlb,andgsnb are preferentially and related proteins in vertebrate model organisms expressed in the adult cornea, whereas gsna is ex- such as zebrafish (Danio rerio), African clawed pressed to a similar extent in the cornea, lens, frogs (Xenopus laevis), chickens (Gallus gallus), brain, and heart (JIA et al. 2007). The authors re- andmice(Mus musculus). We present fundamen- ported that two zebra fish scinl genes are involved tal findings and new scientific data to show the in cornea crystallization. In addition to its accumu- main direction in research and future possibilities. lation in the cornea, the scinla gene is expressed at Our goal was to present the diverse and specific low concentrations during early zebrafish devel- advantages of each animal model in the field of re- opment, where it appears to have a signaling role in search related to gelsolin and gelsolin-family pro- dorsal-ventral patterning. Overexpression of scinla teins. Our summary also underlines the enormous dorsalizes the embryo and can lead to axis duplica- multifunctionality of gelsolin and its specific role tion, while the interruption of scinla expression in numerous biological processes such as develop- with a specific morpholino oligonucleotide ven- ment, morphogenesis, and pathogenesis, which tralizes the embryo, and interferes with brain and makes gelsolin a potential candidate for diverse eye development (KANUNGO et al. 2003, 2004; therapeutic applications. JIA et al. 2007). In contrast to the effect of knocking down scinla Zebrafish (Danio rerio) expression, it has been shown that reducing scinlb expression does not affect dorsal-ventral signaling Based on the gelsolin domains in zebrafish, phy- (JIA et al. 2009). However, the phenotypes with logenetic analysis revealed that there are six genes low scinlb expression exhibited a subtle change in encoding gelsolin-like proteins: the gsna and gsnb the structure of the developing brain that was asso- group with the vertebrate gelsolin gene, scina and ciated with increased cell
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