Benutzer:Petra Delius/Gelsolin
| Gelsolin | ||
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| Bändermodell humanes Gelsolin (PDB 3FFN).[1] Domains 1-6 in verschiedenen Farben dargestellt. | ||
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Vorhandene Strukturdaten: 3FFN | ||
| Masse/Länge Primärstruktur | 782 Aminosäuren | |
| Kofaktor | Ca2+ | |
Gelsolin ist ein Protein, das im Cytoplasma und Mitochondrien von Wirbeltierzellen vorkommt.[2] Die Hauptaufgabe des Gelsolins ist die Spaltung von Aktinfilamenten und die Kontrolle der Polymerisationsdynamik von Aktin.[3][4]
Gelsolin is an actin-binding protein that is a key regulator of actin filament assembly and disassembly. Gelsolin is one of the most potent members of the actin-severing gelsolin/villin superfamily, as it severs with nearly 100% efficiency.[5][6]
Cellular gelsolin, found within the cytosol and mitochondria,[7] has a closely related secreted form, Plasma gelsolin, that contains an additional 24 AA N-terminal extension.[8][9] Plasma gelsolin's ability to sever actin filaments helps the body recover from disease and injury that leaks cellular actin into the blood. Additionally it plays important roles in host innate immunity, activating macrophages and localizing of inflammation.
Structure
[Bearbeiten | Quelltext bearbeiten]Gelsolin is an 82-kD protein with six homologous subdomains, referred to as S1-S6. Each subdomain is composed of a five-stranded β-sheet, flanked by two α-helices, one positioned perpendicular with respect to the strands and one positioned parallel. The β-sheets of the three N-terminal subdomains (S1-S3) join to form an extended β-sheet, as do the β-sheets of the C-terminal subdomains (S4-S6).[10]
Regulation
[Bearbeiten | Quelltext bearbeiten]Among the lipid-binding actin regulatory proteins, gelsolin (like cofilin) preferentially binds polyphosphoinositide (PPI).[11] The binding sequences in gelsolin closely resemble the motifs in the other PPI-binding proteins.[11]
Gelsolin's activity is stimulated by calcium ions (Ca2+).[6] Although the protein retains its overall structural integrity in both activated and deactivated states, the S6 helical tail moves like a latch depending on the concentration of calcium ions.[12] The C-terminal end detects the calcium concentration within the cell. When there is no Ca2+ present, the tail of S6 shields the actin-binding sites on one of S2's helices.[10] When a calcium ion attaches to the S6 tail, however, it straightens, exposing the S2 actin-binding sites.[12] The N-terminal is directly involved in the severing of actin. S2 and S3 bind to the actin before the binding of S1 severs actin-actin bonds and caps the barbed end.[11]
Gelsolin can be inhibited by a local rise in the concentration of phosphatidylinositol (4,5)-bisphosphate (PIP2), a PPI. This is a two step process. Firstly, (PIP2) binds to S2 and S3, inhibiting gelsolin from actin side binding. Then, (PIP2) binds to gelsolin’s S1, preventing gelsolin from severing actin, although (PIP2) does not bind directly to gelsolin's actin-binding site.[11]
Gelsolin's severing of actin, in contrast to the severing of microtubules by katanin, does not require any extra energy input.
Cellular function
[Bearbeiten | Quelltext bearbeiten]As an important actin regulator, gelsolin plays a role in podosome formation (along with Arp3, cortactin, and Rho GTPases).[13]
Gelsolin also inhibits apoptosis by stabilizing the mitochondria.[7] Prior to cell death, mitochondria normally lose membrane potential and become more permeable. Gelsolin can impede the release of cytochrome C, obstructing the signal amplification that would have led to apoptosis.[14]
Actin can be cross-linked into a gel by actin cross-linking proteins. Gelsolin can turn this gel into a sol, hence the name gelsolin.
Animal studies
[Bearbeiten | Quelltext bearbeiten]Research in mice suggests that gelsolin, like other actin-severing proteins, is not expressed to a significant degree until after the early embryonic stage—approximately 2 weeks in murine embryos.[15] In adult specimens, however, gelsolin is particularly important in motile cells, such as blood platelets. Mice with null gelsolin-coding genes undergo normal embryonic development, but the deformation of their blood platelets reduced their motility, resulting in a slower response to wound healing.[15]
An insufficiency of gelsolin in mice has also been shown to cause increased permeability of the vascular pulmonary barrier, suggesting that gelsolin is important in the response to lung injury.[16]
Related proteins
[Bearbeiten | Quelltext bearbeiten]Vorlage:Infobox protein family Sequence comparisons indicate an evolutionary relationship between gelsolin, villin, fragmin, and severin.[17] Six large repeating segments occur in gelsolin and villin, and 3 similar segments in severin and fragmin. The multiple repeats are related in structure (but barely in sequence) to the ADF-H domain, forming a superfamily (InterPro: IPR029006 (englisch)). The family appears to have evolved from an ancestral sequence of 120 to 130 amino acid residues.[17][5]
Asgard archaea encode many functional gelsolins.[18]
Interactions
[Bearbeiten | Quelltext bearbeiten]Gelsolin is a cytoplasmic, calcium-regulated, actin-modulating protein that binds to the barbed ends of actin filaments, preventing monomer exchange (end-blocking or capping).[19] It can promote nucleation (the assembly of monomers into filaments), as well as sever existing filaments. In addition, this protein binds with high affinity to fibronectin. Plasma gelsolin and cytoplasmic gelsolin are derived from a single gene by alternate initiation sites and differential splicing.[8]
Gelsolin has been shown to interact with:
Einzelnachweise
[Bearbeiten | Quelltext bearbeiten]- ↑ RCSB Protein Data Bank: RCSB PDB - 3FFN: Crystal structure of calcium-free human gelsolin. Abgerufen am 29. März 2023 (amerikanisches Englisch).
- ↑ Gelsolin. In: Lexikon der Biologie, Spektrum. Abgerufen am 29. März 2023.
- ↑ Matthias Martin Meyer-Delpho: Gelsolin und Gelsolinspaltprodukte im Plasma von Patienten nach kardiopulmonaler Reanimation bei Myokardinfarkt. In: Dissertation. 2007 (uni-bonn.de [abgerufen am 29. März 2023] Universitäts- und Landesbibliothek Bonn).
- ↑ Leslie D. Burtnick, Robert C. Robinson, Senyon Choe: Structure and Function of Gelsolin. In: Molecular Interactions of Actin: Actin Structure and Actin-Binding Proteins. Springer, Berlin, Heidelberg 2001, ISBN 978-3-540-46560-7, S. 201–211, doi:10.1007/978-3-540-46560-7_14.
- ↑ a b Ghoshdastider U, Popp D, Burtnick LD, Robinson RC: The expanding superfamily of gelsolin homology domain proteins. In: Cytoskeleton. 70. Jahrgang, Nr. 11, November 2013, S. 775–95, doi:10.1002/cm.21149, PMID 24155256.
- ↑ a b Sun HQ, Yamamoto M, Mejillano M, Yin HL: Gelsolin, a multifunctional actin regulatory protein. In: The Journal of Biological Chemistry. 274. Jahrgang, Nr. 47, November 1999, S. 33179–82, doi:10.1074/jbc.274.47.33179, PMID 10559185.
- ↑ a b Koya RC, Fujita H, Shimizu S, Ohtsu M, Takimoto M, Tsujimoto Y, Kuzumaki N: Gelsolin inhibits apoptosis by blocking mitochondrial membrane potential loss and cytochrome c release. In: The Journal of Biological Chemistry. 275. Jahrgang, Nr. 20, Mai 2000, S. 15343–9, doi:10.1074/jbc.275.20.15343, PMID 10809769.
- ↑ a b Kwiatkowski DJ, Stossel TP, Orkin SH, Mole JE, Colten HR, Yin HL: Plasma and cytoplasmic gelsolins are encoded by a single gene and contain a duplicated actin-binding domain. In: Nature. 323. Jahrgang, Nr. 6087, 2. Oktober 1986, S. 455–8, doi:10.1038/323455a0, PMID 3020431, bibcode:1986Natur.323..455K.
- ↑ Nag S, Larsson M, Robinson RC, Burtnick LD: Gelsolin: the tail of a molecular gymnast. In: Cytoskeleton. 70. Jahrgang, Nr. 7, Juli 2013, S. 360–84, doi:10.1002/cm.21117, PMID 23749648.
- ↑ a b Kiselar JG, Janmey PA, Almo SC, Chance MR: Visualizing the Ca2+-dependent activation of gelsolin by using synchrotron footprinting. In: Proceedings of the National Academy of Sciences of the United States of America. 100. Jahrgang, Nr. 7, April 2003, S. 3942–7, doi:10.1073/pnas.0736004100, PMID 12655044, PMC 153027 (freier Volltext), bibcode:2003PNAS..100.3942K.
- ↑ a b c d Yu FX, Sun HQ, Janmey PA, Yin HL: Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. In: The Journal of Biological Chemistry. 267. Jahrgang, Nr. 21, Juli 1992, S. 14616–21, doi:10.1016/S0021-9258(18)42086-8, PMID 1321812.
- ↑ a b Burtnick LD, Urosev D, Irobi E, Narayan K, Robinson RC: Structure of the N-terminal half of gelsolin bound to actin: roles in severing, apoptosis and FAF. In: The EMBO Journal. 23. Jahrgang, Nr. 14, Juli 2004, S. 2713–22, doi:10.1038/sj.emboj.7600280, PMID 15215896, PMC 514944 (freier Volltext).
- ↑ Varon C, Tatin F, Moreau V, Van Obberghen-Schilling E, Fernandez-Sauze S, Reuzeau E, Kramer I, Génot E: Transforming growth factor beta induces rosettes of podosomes in primary aortic endothelial cells. In: Molecular and Cellular Biology. 26. Jahrgang, Nr. 9, Mai 2006, S. 3582–94, doi:10.1128/MCB.26.9.3582-3594.2006, PMID 16611998, PMC 1447430 (freier Volltext).
- ↑ a b Kusano H, Shimizu S, Koya RC, Fujita H, Kamada S, Kuzumaki N, Tsujimoto Y: Human gelsolin prevents apoptosis by inhibiting apoptotic mitochondrial changes via closing VDAC. In: Oncogene. 19. Jahrgang, Nr. 42, Oktober 2000, S. 4807–14, doi:10.1038/sj.onc.1203868, PMID 11039896.
- ↑ a b Witke W, Sharpe AH, Hartwig JH, Azuma T, Stossel TP, Kwiatkowski DJ: Hemostatic, inflammatory, and fibroblast responses are blunted in mice lacking gelsolin. In: Cell. 81. Jahrgang, Nr. 1, April 1995, S. 41–51, doi:10.1016/0092-8674(95)90369-0, PMID 7720072.
- ↑ Becker PM, Kazi AA, Wadgaonkar R, Pearse DB, Kwiatkowski D, Garcia JG: Pulmonary vascular permeability and ischemic injury in gelsolin-deficient mice. In: American Journal of Respiratory Cell and Molecular Biology. 28. Jahrgang, Nr. 4, April 2003, S. 478–84, doi:10.1165/rcmb.2002-0024OC, PMID 12654637.
- ↑ a b Way M, Weeds A: Nucleotide sequence of pig plasma gelsolin. Comparison of protein sequence with human gelsolin and other actin-severing proteins shows strong homologies and evidence for large internal repeats. In: Journal of Molecular Biology. 203. Jahrgang, Nr. 4, Oktober 1988, S. 1127–33, doi:10.1016/0022-2836(88)90132-5, PMID 2850369.
- ↑ Akıl C, Tran LT, Orhant-Prioux M, Baskaran Y, Manser E, Blanchoin L, Robinson RC: Insights into the evolution of regulated actin dynamics via characterization of primitive gelsolin/cofilin proteins from Asgard archaea. In: Proceedings of the National Academy of Sciences of the United States of America. 117. Jahrgang, Nr. 33, August 2020, S. 19904–19913, doi:10.1073/pnas.2009167117, PMID 32747565, PMC 7444086 (freier Volltext), bibcode:2020PNAS..11719904A.
- ↑ Weeds AG, Gooch J, Pope B, Harris HE: Preparation and characterization of pig plasma and platelet gelsolins. In: European Journal of Biochemistry. 161. Jahrgang, Nr. 1, November 1986, S. 69–76, doi:10.1111/j.1432-1033.1986.tb10125.x, PMID 3023087.
- ↑ Chauhan VP, Ray I, Chauhan A, Wisniewski HM: Binding of gelsolin, a secretory protein, to amyloid beta-protein. In: Biochemical and Biophysical Research Communications. 258. Jahrgang, Nr. 2, Mai 1999, S. 241–6, doi:10.1006/bbrc.1999.0623, PMID 10329371.
- ↑ Nishimura K, Ting HJ, Harada Y, Tokizane T, Nonomura N, Kang HY, Chang HC, Yeh S, Miyamoto H, Shin M, Aozasa K, Okuyama A, Chang C: Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator. In: Cancer Research. 63. Jahrgang, Nr. 16, August 2003, S. 4888–94, PMID 12941811.
- ↑ Wang Q, Xie Y, Du QS, Wu XJ, Feng X, Mei L, McDonald JM, Xiong WC: Regulation of the formation of osteoclastic actin rings by proline-rich tyrosine kinase 2 interacting with gelsolin. In: The Journal of Cell Biology. 160. Jahrgang, Nr. 4, Februar 2003, S. 565–75, doi:10.1083/jcb.200207036, PMID 12578912, PMC 2173747 (freier Volltext).