title: Mechanistic basis of desmosome-targeted diseases.
abstract: Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life-threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here, we review a set of newly discovered pathogenic alterations and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualized by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures, and stabilities of folded domains that have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small-angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modeling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues.
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
authors.forename: Caezar
authors.initials: C
authors.lastname: Al-Jassar
authors.forename: Hennie
authors.initials: H
authors.lastname: Bikker
authors.forename: Michael
authors.initials: M
authors.lastname: Overduin
authors.forename: Martyn
authors.initials: M
authors.lastname: Chidgey
mesh_terms: D000818:Animals; D051180:Desmoplakins / Q000235:genetics; D003896:Desmosomes / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation; D051191:Plakophilins / Q000235:genetics; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics*
chemical_list: D051180:Desmoplakins; D051191:Plakophilins
keywords: ARVC; DIFC; EC; EGFR; IA; ICS; Lef; NMD; PPAR; PRD; SH3; SR; Src homology 3; T-cell factor; Tcf; arrhythmogenic right ventricular cardiomyopathy; desmoplakin; desmosomal cadherin; desmosome; desmosome–intermediate filament complex; epidermal growth factor receptor; extracellular cadherin; iPSC; induced pluripotent stem cell; intracellular anchor; intracellular cadherin-typical sequence; lymphoid enhancer factor; nonsense-mediated RNA decay; peroxisome proliferator-activated receptor; plakin repeat domain; plakoglobin; spectrin repeat
references.citation: J Cell Biol. 1997 Nov 3;139(3):773-84
references.pmid: 9348293
references.citation: Mol Cell Biol. 2008 Jan;28(2):825-35
references.pmid: 17984222
references.citation: J Cell Biol. 2008 May 19;181(4):605-13
references.pmid: 18474624
references.citation: Hum Mol Genet. 2013 Feb 1;22(3):531-43
references.pmid: 23108156
references.citation: EMBO J. 2004 Sep 15;23(18):3583-8
references.pmid: 15318169
references.citation: J Cell Biol. 2000 Apr 3;149(1):209-22
references.pmid: 10747098
references.citation: Circ Res. 2006 Sep 15;99(6):646-55
references.pmid: 16917092
references.citation: Br J Dermatol. 2011 Oct;165(4):917-21
references.pmid: 21668431
references.citation: Heart Rhythm. 2011 Nov;8(11):1686-95
references.pmid: 21723241
references.citation: J Proteome Res. 2005 Sep-Oct;4(5):1661-71
references.pmid: 16212419
references.citation: J Struct Biol. 2000 Dec;132(3):169-78
references.pmid: 11243886
references.citation: Oncogene. 2007 Jan 18;26(3):467-76
references.pmid: 16878157
references.citation: J Invest Dermatol. 2009 Sep;129(9):2309-12
references.pmid: 19282843
references.citation: Cardiovasc Res. 2012 Sep 1;95(4):409-18
references.pmid: 22764152
references.citation: Cancer Res. 2005 Mar 15;65(6):2130-8
references.pmid: 15781623
references.citation: Structure. 2011 Feb 9;19(2):244-56
references.pmid: 21300292
references.citation: Mol Biol Cell. 2000 Mar;11(3):1077-92
references.pmid: 10712521
references.citation: J Biol Chem. 1989 May 15;264(14):8310-8
references.pmid: 2470743
references.citation: J Cell Biol. 1996 Nov;135(4):1009-25
references.pmid: 8922383
references.citation: Nat Protoc. 2009;4(3):363-71
references.pmid: 19247286
references.citation: Proc Natl Acad Sci U S A. 2010 Oct 12;107(41):17592-7
references.pmid: 20876147
references.citation: Cell Growth Differ. 1999 Jun;10(6):369-76
references.pmid: 10392898
references.citation: J Cell Biol. 1993 Nov;123(3):691-705
references.pmid: 7693716
references.citation: Science. 1995 Jan 20;267(5196):386-9
references.pmid: 7824937
references.citation: Eur J Cancer. 2006 Sep;42(14):2397-403
references.pmid: 16890424
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11594-9
references.pmid: 19553217
references.citation: Curr Opin Cell Biol. 2002 Oct;14(5):537-45
references.pmid: 12231347
references.citation: J Mol Biol. 2009 Feb 20;386(2):531-43
references.pmid: 19136012
references.citation: Clin Genet. 2010 Jan;77(1):37-48
references.pmid: 19863551
references.citation: J Cell Biol. 2012 Nov 12;199(4):699-711
references.pmid: 23128240
references.citation: Am J Pathol. 2010 May;176(5):2509-19
references.pmid: 20348237
references.citation: Nature. 2012 Dec 6;492(7427):128-32
references.pmid: 23135401
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 19;108(16):6480-5
references.pmid: 21464301
references.citation: Science. 2000 Aug 11;289(5481):950-3
references.pmid: 10937998
references.citation: Hum Mol Genet. 2010 Dec 1;19(23):4595-607
references.pmid: 20829228
references.citation: J Med Genet. 2006 Feb;43(2):e5
references.pmid: 16467215
references.citation: J Cell Sci. 1998 Jul 30;111 ( Pt 14):1941-9
references.pmid: 9645942
references.citation: Am J Cardiol. 2013 Feb 1;111(3):400-5
references.pmid: 23168288
references.citation: Circ Res. 2011 Dec 9;109(12):1342-53
references.pmid: 22021931
references.citation: J Immunol. 2003 Feb 15;170(4):2170-8
references.pmid: 12574390
references.citation: J Clin Invest. 2005 Apr;115(4):888-99
references.pmid: 15841178
references.citation: Nature. 1995 Mar 23;374(6520):327-37
references.pmid: 7885471
references.citation: J Invest Dermatol. 1999 Dec;113(6):940-6
references.pmid: 10594734
references.citation: Heart Rhythm. 2011 Aug;8(8):1214-21
references.pmid: 21397041
references.citation: Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7795-800
references.pmid: 11416169
references.citation: FEBS Lett. 1994 Oct 17;353(2):194-6
references.pmid: 7926050
references.citation: Nature. 2013 Feb 7;494(7435):105-10
references.pmid: 23354045
references.citation: J Cell Sci. 2006 Dec 1;119(Pt 23):4974-85
references.pmid: 17105773
references.citation: J Biol Chem. 2011 Jan 21;286(3):2143-54
references.pmid: 21098030
references.citation: Cell Tissue Res. 2012 May;348(2):249-59
references.pmid: 22293975
references.citation: Matrix Biol. 2010 May;29(4):254-60
references.pmid: 20144712
references.citation: J Am Coll Cardiol. 2010 Feb 9;55(6):587-97
references.pmid: 20152563
references.citation: Hum Pathol. 2009 Sep;40(9):1320-9
references.pmid: 19386346
references.citation: Differentiation. 2004 Oct;72(8):419-33
references.pmid: 15606501
references.citation: Hum Mutat. 2009 Sep;30(9):1278-83
references.pmid: 19569224
references.citation: J Invest Dermatol. 2007 Apr;127(4):775-81
references.pmid: 17195016
references.citation: Am J Hum Genet. 2007 Nov;81(5):964-73
references.pmid: 17924338
references.citation: Biochem J. 2002 Mar 1;362(Pt 2):317-27
references.pmid: 11853539
references.citation: J Biol Chem. 2001 Jul 6;276(27):24871-80
references.pmid: 11335725
references.citation: J Biol Chem. 1996 May 3;271(18):10904-9
references.pmid: 8631907
references.citation: J Clin Invest. 2000 Mar;105(5):625-31
references.pmid: 10712434
references.citation: Heart Rhythm. 2008 Oct;5(10):1455-7
references.pmid: 18672408
references.citation: Cell. 2010 Apr 2;141(1):117-28
references.pmid: 20371349
references.citation: J Biol Chem. 2004 Aug 27;279(35):37191-200
references.pmid: 15205458
references.citation: Hum Mol Genet. 2000 Nov 1;9(18):2761-6
references.pmid: 11063735
references.citation: PLoS One. 2013 Jul 29;8(7):e69767
references.pmid: 23922795
references.citation: J Mol Biol. 2005 Feb 11;346(1):367-76
references.pmid: 15663951
references.citation: Mol Cell Proteomics. 2007 Jun;6(6):1103-9
references.pmid: 17322306
references.citation: J Invest Dermatol. 2012 Apr;132(4):1158-68
references.pmid: 22277941
references.citation: Circulation. 2011 Jun 14;123(23):2690-700
references.pmid: 21606396
references.citation: J Cell Sci. 1999 Dec;112 ( Pt 23):4325-36
references.pmid: 10564650
references.citation: Circ Cardiovasc Genet. 2009 Oct;2(5):428-35
references.pmid: 20031617
references.citation: Circ Cardiovasc Genet. 2010 Aug;3(4):314-22
references.pmid: 20716751
references.citation: J Cardiovasc Transl Res. 2010 Dec;3(6):663-73
references.pmid: 20857253
references.citation: Eur J Cell Biol. 2006 Feb;85(2):69-82
references.pmid: 16406610
references.citation: J Struct Biol. 2004 Nov;148(2):137-52
references.pmid: 15477095
references.citation: Circ Cardiovasc Genet. 2009 Oct;2(5):418-27
references.pmid: 20031616
references.citation: Hum Mol Genet. 2011 May 1;20(9):1811-9
references.pmid: 21320868
references.citation: J Cell Biol. 1992 Mar;116(5):1197-209
references.pmid: 1740472
references.citation: Europace. 2010 Jun;12(6):861-8
references.pmid: 20400443
references.citation: Prog Biophys Mol Biol. 2012 Oct-Nov;110(2-3):340-6
references.pmid: 22944071
references.citation: Cell Adh Migr. 2009 Apr-Jun;3(2):148-54
references.pmid: 19458482
references.citation: J Cell Biol. 2003 Apr 28;161(2):403-16
references.pmid: 12707304
references.citation: J Exp Med. 2009 Aug 3;206(8):1787-802
references.pmid: 19635863
references.citation: Eur J Cell Biol. 2006 Jun;85(6):469-85
references.pmid: 16600422
references.citation: Science. 2003 Oct 3;302(5642):109-13
references.pmid: 14526082
references.citation: Heart Rhythm. 2010 Oct;7(10):1446-53
references.pmid: 20708101
references.citation: Curr Opin Cell Biol. 2004 Oct;16(5):536-43
references.pmid: 15363804
references.citation: Science. 1969 Aug 8;165(3893):597-9
references.pmid: 5815840
references.citation: J Cell Biol. 1994 Oct;127(1):151-60
references.pmid: 7929560
references.citation: Mol Cell Biol. 2011 Mar;31(6):1134-44
references.pmid: 21245375
references.citation: Nature. 2007 Dec 6;450(7171):832-7
references.pmid: 18064004
references.citation: Science. 2002 May 17;296(5571):1308-13
references.pmid: 11964443
references.citation: J Exp Med. 2003 Jun 2;197(11):1501-10
references.pmid: 12771179
references.citation: J Pathol. 2005 Oct;207(2):199-206
references.pmid: 16025435
references.citation: Hum Mol Genet. 2011 Dec 1;20(23):4582-96
references.pmid: 21880664
references.citation: J Mol Biol. 2007 May 18;368(5):1379-91
references.pmid: 17397861
references.citation: Hum Mol Genet. 1999 Jan;8(1):143-8
references.pmid: 9887343
references.citation: BMC Med Genet. 2007 Oct 26;8:65
references.pmid: 17963498
references.citation: J Biol Chem. 2002 Mar 22;277(12):10512-22
references.pmid: 11790773
references.citation: Br J Dermatol. 2010 Jun;162(6):1242-50
references.pmid: 20163417
references.citation: J Formos Med Assoc. 2008 Jul;107(7):548-58
references.pmid: 18632414
references.citation: J Biol Chem. 1990 Jul 5;265(19):11406-7
references.pmid: 2391353
references.citation: J Cutan Pathol. 2003 Nov;30(10):621-30
references.pmid: 14744087
references.citation: Breast Cancer Res. 2005;7(5):R669-80
references.pmid: 16168112
references.citation: J Invest Dermatol. 2005 Apr;124(4):764-77
references.pmid: 15816835
references.citation: J Clin Invest. 2005 Nov;115(11):3157-65
references.pmid: 16211092
references.citation: Cell. 2012 Jun 8;149(6):1192-205
references.pmid: 22682243
references.citation: Nature. 1996 Mar 28;380(6572):360-4
references.pmid: 8598933
references.citation: J Biol Chem. 2009 Nov 13;284(46):31776-88
references.pmid: 19759396
references.citation: J Mol Biol. 2011 Jun 24;409(5):800-12
references.pmid: 21536047
references.citation: J Mol Biol. 2011 Sep 2;411(5):1049-61
references.pmid: 21756917
references.citation: J Cell Biol. 1997 Jul 14;138(1):193-201
references.pmid: 9214392
references.citation: Mol Biol Cell. 2003 May;14(5):1978-92
references.pmid: 12802069
references.citation: Cell Commun Adhes. 2009;16(1-3):15-27
references.pmid: 19533476
references.citation: Biochim Biophys Acta. 2008 Mar;1778(3):572-87
references.pmid: 17854763
references.citation: Cell. 2006 Nov 3;127(3):635-48
references.pmid: 17081983
references.citation: Eur Heart J. 2006 Aug;27(15):1847-54
references.pmid: 16774985
references.citation: Am J Cardiol. 2012 Jan 15;109(2):272-5
references.pmid: 22036107
references.citation: Cold Spring Harb Perspect Biol. 2009 Sep;1(3):a003053
references.pmid: 20066110
references.citation: Eur Heart J. 2007 Mar;28(5):581-8
references.pmid: 17105751
references.citation: Nat Struct Biol. 2002 Aug;9(8):612-20
references.pmid: 12101406
references.citation: Am J Hum Genet. 2006 Jul;79(1):136-42
references.pmid: 16773573
references.citation: Mol Cell Biol. 2003 Oct;23(20):7391-402
references.pmid: 14517306
references.citation: Br J Cancer. 2006 Nov 20;95(10):1367-70
references.pmid: 17088906
references.citation: J Cell Biol. 1963 May;17:375-412
references.pmid: 13944428
references.citation: J Cell Sci. 1986 Sep;85:113-24
references.pmid: 3793787
references.citation: Prog Biophys Mol Biol. 1973;26:45-101
references.pmid: 4122630
references.citation: Nat Genet. 1997 Oct;17(2):240-4
references.pmid: 9326952
references.citation: J Biol Chem. 1994 Nov 25;269(47):29351-4
references.pmid: 7525582
references.citation: J Immunol. 2008 Aug 1;181(3):1825-34
references.pmid: 18641320
references.citation: Exp Cell Res. 2003 Apr 15;285(1):114-30
references.pmid: 12681292
references.citation: N Engl J Med. 2009 Mar 12;360(11):1075-84
references.pmid: 19279339
references.citation: J Clin Invest. 2012 Oct;122(10):3781-90
references.pmid: 22996451
references.citation: Circulation. 2006 Mar 7;113(9):1171-9
references.pmid: 16505173
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):5834-9
references.pmid: 12719544
references.citation: J Biol Chem. 2006 Mar 17;281(11):7623-34
references.pmid: 16377623
references.citation: J Clin Invest. 2009 Jul;119(7):1806-13
references.pmid: 19587455
references.citation: Nat Rev Cancer. 2011 May;11(5):317-23
references.pmid: 21508970
references.citation: Cardiovasc Pathol. 2012 Jul-Aug;21(4):275-82
references.pmid: 22036071
references.citation: Cancer Res. 2005 Aug 15;65(16):7102-10
references.pmid: 16103059
references.citation: Cell Tissue Res. 1997 Dec;290(3):481-99
references.pmid: 9369526
references.citation: J Med Genet. 2010 Nov;47(11):736-44
references.pmid: 20864495
references.citation: Cell. 2001 May 4;105(3):391-402
references.pmid: 11348595
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 17;109(3):E127-34
references.pmid: 22171007
references.citation: Exp Cell Res. 2010 Feb 15;316(4):580-92
references.pmid: 19818770
references.citation: J Invest Dermatol. 2002 Feb;118(2):232-8
references.pmid: 11841538
references.citation: Lancet. 2000 Jun 17;355(9221):2119-24
references.pmid: 10902626
references.citation: Circ Cardiovasc Genet. 2012 Aug 1;5(4):400-11
references.pmid: 22781308
references.citation: J Clin Invest. 2006 Jul;116(7):2012-21
references.pmid: 16823493
references.citation: Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7701-5
references.pmid: 8755539
references.citation: Eur J Hum Genet. 2010 Jul;18(7):776-82
references.pmid: 20197793
references.citation: Am J Hum Genet. 2005 Oct;77(4):653-60
references.pmid: 16175511