Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics

Dieding M, Debus JD, Kerkhoff R, Gärtner-Rommel A, Walhorn V, Milting H, Anselmetti D (2017)
Scientific Reports 7(1): 13791.

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Zeitschriftenaufsatz | Veröffentlicht | Englisch
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Abstract / Bemerkung
Cadherins are calcium dependent adhesion proteins that establish the intercellular mechanical contact by bridging the gap to adjacent cells. Desmoglein-2 (Dsg2) is a specific cadherin of the cell-cell contact in cardiac desmosomes. Mutations in the DSG2-gene are regarded to cause arrhythmogenic (right ventricular) cardiomyopathy (ARVC) which is a rare but severe heart muscle disease. The molecular pathomechanisms of the vast majority of DSG2 mutations, however, are unknown. Here, we investigated the homophilic binding of wildtype Dsg2 and two mutations which are associated with ARVC. Using single molecule force spectroscopy and applying Jarzynski's equality we determined the kinetics and thermodynamics of Dsg2 homophilic binding. Notably, the free energy landscape of Dsg2 dimerization exposes a high activation barrier which is in line with the proposed strand-swapping binding motif. Although the binding motif is not directly affected by the mutations the binding kinetics differ significantly from the wildtype. Furthermore, we applied a dispase based cell dissociation assay using HT1080 cell lines over expressing Dsg2 wildtype and mutants, respectively. Our molecular and cellular results consistently demonstrate that Dsg2 mutations can heavily affect homophilic Dsg2 interactions. Furthermore, the full thermodynamic and kinetic description of Dsg2 dimerization provides a consistent model of the so far discussed homophilic cadherin binding.
Erscheinungsjahr
Zeitschriftentitel
Scientific Reports
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7
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1
Art.-Nr.
13791
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Dieding M, Debus JD, Kerkhoff R, et al. Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Scientific Reports. 2017;7(1): 13791.
Dieding, M., Debus, J. D., Kerkhoff, R., Gärtner-Rommel, A., Walhorn, V., Milting, H., & Anselmetti, D. (2017). Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Scientific Reports, 7(1), 13791. doi:10.1038/s41598-017-13737-x
Dieding, M., Debus, J. D., Kerkhoff, R., Gärtner-Rommel, A., Walhorn, V., Milting, H., and Anselmetti, D. (2017). Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Scientific Reports 7:13791.
Dieding, M., et al., 2017. Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Scientific Reports, 7(1): 13791.
M. Dieding, et al., “Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics”, Scientific Reports, vol. 7, 2017, : 13791.
Dieding, M., Debus, J.D., Kerkhoff, R., Gärtner-Rommel, A., Walhorn, V., Milting, H., Anselmetti, D.: Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics. Scientific Reports. 7, : 13791 (2017).
Dieding, Mareike, Debus, Jana Davina, Kerkhoff, Raimund, Gärtner-Rommel, Anna, Walhorn, Volker, Milting, Hendrik, and Anselmetti, Dario. “Arrhythmogenic cardiomyopathy related DSG2 mutations affect desmosomal cadherin binding kinetics”. Scientific Reports 7.1 (2017): 13791.

4 Zitationen in Europe PMC

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Atomic Force Microscopy Provides New Mechanistic Insights into the Pathogenesis of Pemphigus.
Vielmuth F, Spindler V, Waschke J., Front Immunol 9(), 2018
PMID: 29643851
Molecular insights into cardiomyopathies associated with desmin (DES) mutations.
Brodehl A, Gaertner-Rommel A, Milting H., Biophys Rev 10(4), 2018
PMID: 29926427
Genetics of and pathogenic mechanisms in arrhythmogenic right ventricular cardiomyopathy.
Vimalanathan AK, Ehler E, Gehmlich K., Biophys Rev 10(4), 2018
PMID: 29995277
Exploring the Sulfatase 1 Catch Bond Free Energy Landscape using Jarzynski's Equality.
Walhorn V, Möller AK, Bartz C, Dierks T, Anselmetti D., Sci Rep 8(1), 2018
PMID: 30442949

38 References

Daten bereitgestellt von Europe PubMed Central.

The extracellular architecture of adherens junctions revealed by crystal structures of type I cadherins.
Harrison OJ, Jin X, Hong S, Bahna F, Ahlsen G, Brasch J, Wu Y, Vendome J, Felsovalyi K, Hampton CM, Troyanovsky RB, Ben-Shaul A, Frank J, Troyanovsky SM, Shapiro L, Honig B., Structure 19(2), 2011
PMID: 21300292
The molecular architecture of cadherins in native epidermal desmosomes.
Al-Amoudi A, Diez DC, Betts MJ, Frangakis AS., Nature 450(7171), 2007
PMID: 18064004
Cadherin flexibility provides a key difference between desmosomes and adherens junctions.
Tariq H, Bella J, Jowitt TA, Holmes DF, Rouhi M, Nie Z, Baldock C, Garrod D, Tabernero L., Proc. Natl. Acad. Sci. U.S.A. 112(17), 2015
PMID: 25855637
Thinking outside the cell: how cadherins drive adhesion.
Brasch J, Harrison OJ, Honig B, Shapiro L., Trends Cell Biol. 22(6), 2012
PMID: 22555008
Cadherin-mediated cell-cell adhesion: sticking together as a family.
Patel SD, Chen CP, Bahna F, Honig B, Shapiro L., Curr. Opin. Struct. Biol. 13(6), 2003
PMID: 14675546
Specificity of cell-cell adhesion by classical cadherins: Critical role for low-affinity dimerization through beta-strand swapping.
Chen CP, Posy S, Ben-Shaul A, Shapiro L, Honig BH., Proc. Natl. Acad. Sci. U.S.A. 102(24), 2005
PMID: 15937105
Homophilic interactions between cadherin fragments at the single molecule level: an AFM study.
du Roure O, Buguin A, Feracci H, Silberzan P., Langmuir 22(10), 2006
PMID: 16649782
Desmoglein 2-mediated adhesion is required for intestinal epithelial barrier integrity.
Schlegel N, Meir M, Heupel WM, Holthofer B, Leube RE, Waschke J., Am. J. Physiol. Gastrointest. Liver Physiol. 298(5), 2010
PMID: 20224006
Imaging and force spectroscopy on desmoglein 1 using atomic force microscopy reveal multivalent Ca(2+)-dependent, low-affinity trans-interaction.
Waschke J, Menendez-Castro C, Bruggeman P, Koob R, Amagai M, Gruber HJ, Drenckhahn D, Baumgartner W., J. Membr. Biol. 216(2-3), 2007
PMID: 17657525
Data analysis of interaction forces measured with the atomic force microscope
Baumgartner W, Hinterdorfer P, Schindler H., Ultramicroscopy 82(1-4), 2000
PMID: 10741656
Allosteric cross talk between cadherin extracellular domains.
Shi Q, Maruthamuthu V, Li F, Leckband D., Biophys. J. 99(1), 2010
PMID: 20655837
Structural basis of adhesive binding by desmocollins and desmogleins.
Harrison OJ, Brasch J, Lasso G, Katsamba PS, Ahlsen G, Honig B, Shapiro L., Proc. Natl. Acad. Sci. U.S.A. 113(26), 2016
PMID: 27298358
Contemporary definitions and classification of the cardiomyopathies: an American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention.
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB; American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention., Circulation 113(14), 2006
PMID: 16567565
Equilibrium free-energy differences from nonequilibrium measurements: A master-equation approach
Jarzynski C., 1997
Deciphering the scaling of single-molecule interactions using Jarzynski's equality.
Raman S, Utzig T, Baimpos T, Ratna Shrestha B, Valtiner M., Nat Commun 5(), 2014
PMID: 25412574
Calcium-dependent homoassociation of E-cadherin by NMR spectroscopy: changes in mobility, conformation and mapping of contact regions.
Haussinger D, Ahrens T, Sass HJ, Pertz O, Engel J, Grzesiek S., J. Mol. Biol. 324(4), 2002
PMID: 12460580
Kinetics of protein-protein association explained by Brownian dynamics computer simulation.
Northrup SH, Erickson HP., Proc. Natl. Acad. Sci. U.S.A. 89(8), 1992
PMID: 1565624
Cadherin interaction probed by atomic force microscopy.
Baumgartner W, Hinterdorfer P, Ness W, Raab A, Vestweber D, Schindler H, Drenckhahn D., Proc. Natl. Acad. Sci. U.S.A. 97(8), 2000
PMID: 10759550
Ca2+ dependency of N-cadherin function probed by laser tweezer and atomic force microscopy.
Baumgartner W, Golenhofen N, Grundhofer N, Wiegand J, Drenckhahn D., J. Neurosci. 23(35), 2003
PMID: 14657157
Ideal, catch, and slip bonds in cadherin adhesion.
Rakshit S, Zhang Y, Manibog K, Shafraz O, Sivasankar S., Proc. Natl. Acad. Sci. U.S.A. 109(46), 2012
PMID: 23112161
Different roles of cadherins in the assembly and structural integrity of the desmosome complex.
Lowndes M, Rakshit S, Shafraz O, Borghi N, Harmon RM, Green KJ, Sivasankar S, Nelson WJ., J. Cell. Sci. 127(Pt 10), 2014
PMID: 24610950
Molecular design principles underlying β-strand swapping in the adhesive dimerization of cadherins.
Vendome J, Posy S, Jin X, Bahna F, Ahlsen G, Shapiro L, Honig B., Nat. Struct. Mol. Biol. 18(6), 2011
PMID: 21572446
The allosteric role of the Ca2+ switch in adhesion and elasticity of C-cadherin.
Sotomayor M, Schulten K., Biophys. J. 94(12), 2008
PMID: 18326636
In vitro functional analyses of arrhythmogenic right ventricular cardiomyopathy-associated desmoglein-2-missense variations.
Gaertner A, Klauke B, Stork I, Niehaus K, Niemann G, Gummert J, Milting H., PLoS ONE 7(10), 2012
PMID: 23071725
Calibration of atomic–force microscope tips
Hutter JL, Bechhoefer J., 1993
Remarks on some nonparametric estimates of a density function
Rosenblatt M., 1956
On estimation of a probability density function and mode
Parzen E., 1962

AUTHOR UNKNOWN, 0

AUTHOR UNKNOWN, 0
Detailed studies of the binding mechanism of the Sinorhizobium meliloti transcriptional activator ExpG to DNA.
Baumgarth B, Bartels FW, Anselmetti D, Becker A, Ros R., Microbiology (Reading, Engl.) 151(Pt 1), 2005
PMID: 15632443
Effector-stimulated single molecule protein-DNA interactions of a quorum-sensing system in Sinorhizobium meliloti.
Bartels FW, McIntosh M, Fuhrmann A, Metzendorf C, Plattner P, Sewald N, Anselmetti D, Ros R, Becker A., Biophys. J. 92(12), 2007
PMID: 17384071
Novel polymer linkers for single molecule AFM force spectroscopy.
Tong Z, Mikheikin A, Krasnoslobodtsev A, Lv Z, Lyubchenko YL., Methods 60(2), 2013
PMID: 23624104
Études de dynamique chimique
van’t MJH., 1884
Über die Dissociationswärme und den Einfluss der Temperatur auf den Dissociationsgrad der Elektrolyte
Arrhenius S., 1889
The activated complex in chemical reactions
Eyring H., 1935
Desmosomal cadherins utilize distinct kinesins for assembly into desmosomes.
Nekrasova OE, Amargo EV, Smith WO, Chen J, Kreitzer GE, Green KJ., J. Cell Biol. 195(7), 2011
PMID: 22184201

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