Calcium‐induced conformational changes in the amino‐terminal half of gelsolin

Roustan, Claude; Ferjani, Imen; Maciver, Sutherland K.; Fattoum, Abdellatif; Rebière, Bertrand; Benyamin, Yves

doi:10.1016/j.febslet.2007.01.031

Cited by 8 publications

(6 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reported calcium‐binding affinities for the type‐2 sites of gelsolin range from 0.2 to 600 μM, for example, K d = 600 μM in G1 [Zapun et al, ], K d = 0.7 μM in G2 [Chen et al, ], unknown K d for G3, K d = 1.8 μM in G4 [Pope et al, ], K d = 100 μM in G5 [Khaitlina et al, ], and K d = 0.2 μM in G6 [Pope et al, ], suggesting that the domains may bind calcium sequentially with increasing calcium concentrations, thus widening the range of calcium concentration to which the protein can respond and fine‐tune its activity. However, one must remember that the local environment modulates the response of this calcium‐sensing domain as evidenced by the variation in the measured K d values depending on whether a given domain is studied in isolation, or in the context of other domains, activators, or in the presence of the target protein, actin [Pope et al, ; Zapun et al, ; Chen et al, ; Chumnarnsilpa et al, ; Roustan et al, ]. Therefore, subtleties of the calcium‐binding process, such as cooperativity or dependence on binding partners, may be obscured in these studies.…”

Section: The Gelsolin Domainmentioning

confidence: 99%

Gelsolin: The tail of a molecular gymnast

et al. 2013

View full text Add to dashboard Cite

Gelsolin superfamily members are Ca 21 -dependent, multidomain regulators of the actin cytoskeleton. Calcium binding activates gelsolin by inducing molecular gymnastics (large-scale conformational changes) that expose actin interaction surfaces by releasing a series of latches. A specialized tail latch has distinguished gelsolin within the superfamily. Active gelsolin exhibits actin filament severing and capping, and actin monomer sequestering activities. Here, we analyze a combination of sequence, structural, biophysical and biochemical data to assess whether the molecular plasticity, regulation and actinrelated properties of gelsolin are also present in other superfamily members. We conclude that all members of the superfamily will be able to transition between a compact conformation and a more open form, and that most of these open forms will interact with actin. Supervillin, which lacks the severing domain 1 and the F-actin binding-site on domain 2, is the clear exception. Eight calcium-binding sites are absolutely conserved in gelsolin, adseverin, advillin and villin, and compromised to increasing degrees in CapG, villin-like protein, supervillin and flightless I. Advillin, villin and supervillin each contain a potential tail latch, which is absent from CapG, adseverin and flightless I, and ambiguous in villin-like protein. Thus, calcium regulation will vary across the superfamily. Potential novel isoforms of the superfamily suggest complex regulation at the gene, transcript and protein levels. We review animal, clinical and cellular data that illuminate how the regulation of molecular flexibility in gelsolin-like proteins permits cells to exploit the force generated from actin polymerization to drive processes such as cell movement in health and disease. V C 2013 Wiley Periodicals, Inc.

show abstract

Section: The Gelsolin Domainmentioning

confidence: 99%

Gelsolin: The tail of a molecular gymnast

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Figure 2A to 2B) and a strand from the β-sheet in G2 is removed with its subsequent reattachment to the β-sheet in G1, thus creating a new interface between G2 and G3 (Figure 2B) (Nag et al, 2009). Binding of calcium to the type 2 binding sites in the other domains stabilizes gelsolin in its open, active conformation (Figure 2B) (Ashish et al, 2007, Lueck et al, 2000, Roustan et al, 2007). …”

Section: The Multiple Structures Of Full-length Gelsolinmentioning

confidence: 99%

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Solomon

Page

Balch

et al. 2012

Critical Reviews in Biochemistry and Molecular Biology

View full text Add to dashboard Cite

Protein misassembly into aggregate structures, including cross-β-sheet amyloid fibrils, is linked to diseases characterized by the degeneration of post-mitotic tissue. While amyloid fibril deposition in the extracellular space certainly disrupts cellular and tissue architecture late in the course of amyloid diseases, strong genetic, pathological and pharmacologic evidence suggests that the process of amyloid fibril formation itself, known as amyloidogenesis, likely causes these maladies. It seems that the formation of oligomeric aggregates during the amyloidogenesis process causes the proteotoxicity and cytotoxicity characteristic of these disorders. Herein, we review what is known about the genetics, biochemistry and pathology of familial amyloidosis of Finnish Type (FAF) or gelsolin amyloidosis. Briefly, autosomal dominant D187N or D187Y mutations compromise Ca2+ binding in domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations. When domain 2 is unfolded, gelsolin is subject to aberrant furin endoproteolysis as it passes through the Golgi on its way to the extracellular space. The resulting C-terminal 68kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin. These amyloidogenic fragments deposit systemically, causing a variety of symptoms, including corneal lattice dystrophy and neurodegeneration. The first murine model of the disease recapitulates the aberrant processing of mutant plasma gelsolin, amyloid deposition, and the degenerative phenotype. We use what we have learned from our biochemical studies, as well as insight from mouse and human pathology to propose therapeutic strategies that may halt the progression of FAF.

show abstract

“…The structural and functional data from the last few decades have suggested that the actin filament-depolymerization activity of gelsolin resides in its N-terminal region, and the N-terminal half (G1-G3) of the molecule can depolymerize filamentous actin as well as cap the barbed end in a calciumindependent but PIP 2 -sensitive manner (6 -10). Despite the lack of absolute control of the depolymerizing activity of G1-G3 by Ca 2ϩ , these divalent ions do regulate the structure of the N-terminal half of gelsolin as evident from dynamic light scattering and fluorescence studies and analysis of its crystal structure (7,11,12). The fluorescence-based kinetic studies have also shown that the Ca 2ϩ binding-triggered conformational changes in G1-G3 enhance its interaction with F-actin, as well as increase its F-actin depolymerizing efficiency.…”

mentioning

confidence: 99%

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Peddada¹,

Sagar²,

Rathore³

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Shape-function studies are necessary to design better therapeutic alternatives of the plasma gelsolin. Results: N-terminal fragment 30 -161 is the smallest segment with F-actin depolymerization potential, and G1-G3 can function independent of Ca 2ϩ ions or low pH. Conclusion: The g2-g3 linker plays a role in imparting pH/Ca 2ϩ insensitivity to G1-G3. Significance: We provide the first evidence that g2-g3 linker regulates mobility of the G1 domain.

show abstract

Calcium‐induced conformational changes in the amino‐terminal half of gelsolin

Cited by 8 publications

References 43 publications

Gelsolin: The tail of a molecular gymnast

Gelsolin: The tail of a molecular gymnast

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention

Global Shapes of F-actin Depolymerization-competent Minimal Gelsolins

Contact Info

Product

Resources

About