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Cell adhesion in desmosomes

Desmoplakin is a protein in humans that is encoded by the DSP gene.^[1]^[2]^[3] Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell contacts. In cardiac muscle, desmoplakin is localized to intercalated discs which mechanically couple cardiac cells to function in a coordinated syncytial structure. Mutations in desmoplakin have been shown to play a role in dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, striate palmoplantar keratoderma, Carvajal syndrome and paraneoplastic pemphigus.

Structure

Desmoplakin exists as two predominant isoforms; the first, known as "DPII", has molecular weight 260.0 kDa (2272 amino acids) and the second, known as "DPI", has molecular weight 332.0 kDa (2871 amino acids).^[4]^[5] These isoforms are identical except for the shorter rod domain in DPII. DPI is the predominant isoform expressed in cardiac muscle.^[6] The DSP gene is located on chromosome 6p24.3, containing 24 exons and spanning approximately 45 kDa of genomic DNA.^[7] Desmoplakin is a large desmosomal plaque protein that homodimerizes and adopts a dumbell-shaped conformation.^[7] The N-terminal globular head domain of desmoplakin is composed of a series of alpha helical bundles, and is required for both the localization to the desmosome and interaction with the N-terminal region of plakophilin 1 and plakoglobin. This is further sub divided into a region called the "Plakin domain" made up of six spectrin repeat domains separated by SH3 domain.^[8] A crystal structure of part of the plakin domain has been resolved,^[9] while the entire plakin domain has been elucidated using small angle X-ray scattering which revealed a non-linear structure, an unexpected result considering spectrin repeats are observed in linear orientations.^[10] The C-terminal region of desmoplakin is composed of three plakin repeat domains, termed A, B and C, which are essential for coalignment and binding of intermediate filaments.^[11]^[12] Located at the most distal C-terminus of desmoplakin is a region rich in glycine–serine–arginine; it has been demonstrated that serine phosphorylation of this domain may modify desmoplakin-intermediate filament interactions.^[13] In the mid-region of desmoplakin, a coiled-coil rod domain is responsible for homodimerization.^[14]

Function

Desmosomes are intercellular junctions that tightly link adjacent cells. Desmoplakin is an obligate component of functional desmosomes that anchors intermediate filaments to desmosomal plaques. In cardiomyocytes, desmoplakin forms desmosomal plaques with the intermediate filament desmin, whereas in endothelial cells cytokeratin type intermediate filaments are recruited, and vimentin in arachnoid and follicular dendritic cell types.^[14]^[15] Both types of intermediate filaments attach in a lateral fashion to desmoplakin to form the plaque.^[16] In cardiac muscle, desmoplakin is localized to desmosomes in intercalated discs. Desmoplakin isoform DPI is highly expressed and is thought to play a role in both the assembly and stabilization of desmosomes; it's role is critical, as desmoplakin knockout mice display embryonic lethality.^[17] In mice overexpressing a C-terminal mutated desmoplakin protein, desmoplakin binding to desmin is disrupted in cardiac muscle and hearts display abnormal intercalated disc formation and structure.^[18] Much has been learned regarding desmoplakin function from mutations in patients with arrhythmogenic right ventricular cardiomyopathy, where mutations in specific binding domains alter desmoplakin binding to plakoglobin or desmin and result in cell death and dysfunction.^[19]

Clinical Significance

Mutations in this gene are the cause of several cardiomyopathies, including dilated cardiomyopathy^[20]^[21] and arrhythmogenic right ventricular cardiomyopathy.^[18]^[22]^[23]^[24]^[25]^[26] Mutations in DSP have also been associated with striate palmoplantar keratoderma.^[20]^[24]^[27]^[28]^[29] Carvajal syndrome results from an autosomal recessive mutation of a frameshift (7901delG) in DSP that results in a combination of above conditions, including dilated cardiomyopathy, keratoderma and woolly hair.^[30] Patients with Carvajal syndrome often suffer from heart failure in teenage years. A case of compound heterozygosity for two DSP nonsense mutations resulting in lethal acantholytic epidermolysis bullosa has been reported.^[31]^[32] Autoantibodies to DSP are a hallmark of the autoimmune disease paraneoplastic pemphigus.^[33]^[34] Decreased desmoplakin expression has been found in patients with oropharyngeal cancer and breast cancer, which may alter cell-cell adhesion properties and propagate metastasis.^[35]^[36]

Interactions

Desmoplakin has been shown to interact with:

Desmin,^[37]
Keratin 1,^[37]
PKP1^[38]
PKP2,^[39]
Plakoglobin,^[40]^[41] and
Vimentin.^[37]

References

^ Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS (October 1991). "Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP)". Genomics 10 (3): 640–5. doi:10.1016/0888-7543(91)90446-L. PMID 1889810.
^ "Entrez Gene: DSP desmoplakin".
^ Bornslaeger EA, Corcoran CM, Stappenbeck TS, Green KJ (August 1996). "Breaking the connection: displacement of the desmosomal plaque protein desmoplakin from cell-cell interfaces disrupts anchorage of intermediate filament bundles and alters intercellular junction assembly". J. Cell Biol. 134 (4): 985–1001. doi:10.1083/jcb.134.4.985. PMC 2120955. PMID 8769422.
^ "Protein sequence of human desmoplakin (Uniprot ID: P15924)". Cardiac Organellar Protein Atlas Knowledgabase (COPaKB). Retrieved 26 June 2015.
^ "Protein sequence of human desmoplakin (Uniprot ID: P15924-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 26 June 2015.
^ Al-Jassar C, Bikker H, Overduin M, Chidgey M (Nov 2013). "Mechanistic basis of desmosome-targeted diseases". Journal of Molecular Biology 425 (21): 4006–22. doi:10.1016/j.jmb.2013.07.035. PMID 23911551.
^ ^a ^b Green KJ, Parry DA, Steinert PM, Virata ML, Wagner RM, Angst BD et al. (Feb 1990). "Structure of the human desmoplakins. Implications for function in the desmosomal plaque". The Journal of Biological Chemistry 265 (5): 2603–12. PMID 1689290.
^ Jefferson JJ, Ciatto C, Shapiro L, Liem RK (Feb 2007). "Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily". Journal of Molecular Biology 366 (1): 244–57. doi:10.1016/j.jmb.2006.11.036. PMID 17161423.
^ Choi HJ, Weis WI (2011). "Crystal structure of a rigid four-spectrin-repeat fragment of the human desmoplakin plakin domain". J. Mol. Biol. 409 (5): 800–12. doi:10.1016/j.jmb.2011.04.046. PMC 3107870. PMID 21536047.
^ Al-Jassar C, Knowles T, Jeeves M, Kami K, Behr E, Bikker H et al. (2011). "The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations". J. Mol. Biol. 411 (5): 1049–61. doi:10.1016/j.jmb.2011.06.047. PMID 21756917.
^ Choi HJ, Park-Snyder S, Pascoe LT, Green KJ, Weis WI (Aug 2002). "Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure". Nature Structural Biology 9 (8): 612–20. doi:10.1038/nsb818. PMID 12101406.
^ Stappenbeck TS, Bornslaeger EA, Corcoran CM, Luu HH, Virata ML, Green KJ (Nov 1993). "Functional analysis of desmoplakin domains: specification of the interaction with keratin versus vimentin intermediate filament networks". The Journal of Cell Biology 123 (3): 691–705. PMID 7693716.
^ Stappenbeck TS, Lamb JA, Corcoran CM, Green KJ (Nov 1994). "Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks". The Journal of Biological Chemistry 269 (47): 29351–4. PMID 7525582.
^ ^a ^b Garrod D, Chidgey M (Mar 2008). "Desmosome structure, composition and function". Biochimica Et Biophysica Acta 1778 (3): 572–87. doi:10.1016/j.bbamem.2007.07.014. PMID 17854763.
^ Kartenbeck J, Schwechheimer K, Moll R, Franke WW (Mar 1984). "Attachment of vimentin filaments to desmosomal plaques in human meningiomal cells and arachnoidal tissue". The Journal of Cell Biology 98 (3): 1072–81. PMID 6365927.
^ Kartenbeck J, Franke WW, Moser JG, Stoffels U (1983). "Specific attachment of desmin filaments to desmosomal plaques in cardiac myocytes". The EMBO Journal 2 (5): 735–42. PMID 6416832.
^ Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L et al. (Dec 1998). "Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage". The Journal of Cell Biology 143 (7): 2009–22. PMID 9864371.
^ ^a ^b Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S et al. (Sep 2006). "Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy". Circulation Research 99 (6): 646–55. doi:10.1161/01.RES.0000241482.19382.c6. PMID 16917092.
^ Awad MM, Calkins H, Judge DP (May 2008). "Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy". Nature Clinical Practice. Cardiovascular Medicine 5 (5): 258–67. doi:10.1038/ncpcardio1182. PMID 18382419.
^ ^a ^b Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE et al. (Nov 2000). "Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma". Human Molecular Genetics 9 (18): 2761–6. PMID 11063735.
^ Carvajal-Huerta L (Sep 1998). "Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy". Journal of the American Academy of Dermatology 39 (3): 418–21. PMID 9738775.
^ Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V et al. (Nov 2002). "Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy". American Journal of Human Genetics 71 (5): 1200–6. doi:10.1086/344208. PMID 12373648.
^ Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (Jul 2003). "A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair". Journal of the American College of Cardiology 42 (2): 319–27. PMID 12875771.
^ ^a ^b Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserili H et al. (Feb 2006). "Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome". Journal of Medical Genetics 43 (2): e5. doi:10.1136/jmg.2005.032904. PMID 16467215.
^ van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H et al. (Sep 2009). "A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy". Human Mutation 30 (9): 1278–83. doi:10.1002/humu.21064. PMID 19569224.
^ Al-Jassar C, Knowles T, Jeeves M, Kami K, Behr E, Bikker H et al. (Sep 2011). "The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations". Journal of Molecular Biology 411 (5): 1049–61. doi:10.1016/j.jmb.2011.06.047. PMID 21756917.
^ Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM et al. (Jan 1999). "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma". Human Molecular Genetics 8 (1): 143–8. PMID 9887343.
^ Whittock NV, Ashton GH, Dopping-Hepenstal PJ, Gratian MJ, Keane FM, Eady RA et al. (Dec 1999). "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency". The Journal of Investigative Dermatology 113 (6): 940–6. doi:10.1046/j.1523-1747.1999.00783.x. PMID 10594734.
^ Whittock NV, Wan H, Morley SM, Garzon MC, Kristal L, Hyde P et al. (Feb 2002). "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome". The Journal of Investigative Dermatology 118 (2): 232–8. doi:10.1046/j.0022-202x.2001.01664.x. PMID 11841538.
^ Carvajal-Huerta L (Sep 1998). "Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy". Journal of the American Academy of Dermatology 39 (3): 418–21. PMID 9738775.
^ Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A et al. (Oct 2005). "Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa". American Journal of Human Genetics 77 (4): 653–60. doi:10.1086/496901. PMID 16175511.
^ McGrath JA, Bolling MC, Jonkman MF (Jan 2010). "Lethal acantholytic epidermolysis bullosa". Dermatologic Clinics 28 (1): 131–5. doi:10.1016/j.det.2009.10.015. PMID 19945626.
^ Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M et al. (Dec 1990). "Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia". The New England Journal of Medicine 323 (25): 1729–35. doi:10.1056/NEJM199012203232503. PMID 2247105.
^ Oursler JR, Labib RS, Ariss-Abdo L, Burke T, O'Keefe EJ, Anhalt GJ (Jun 1992). "Human autoantibodies against desmoplakins in paraneoplastic pemphigus". The Journal of Clinical Investigation 89 (6): 1775–82. doi:10.1172/JCI115781. PMID 1601988.
^ Papagerakis S, Shabana AH, Pollock BH, Papagerakis P, Depondt J, Berdal A (Sep 2009). "Altered desmoplakin expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer". Human Pathology 40 (9): 1320–9. doi:10.1016/j.humpath.2009.02.002. PMID 19386346.
^ Pang H, Rowan BG, Al-Dhaheri M, Faber LE (2004). "Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells". Breast Cancer Research 6 (3): R239–45. doi:10.1186/bcr780. PMID 15084247.
^ ^a ^b ^c Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W (August 1997). "Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments". J. Biol. Chem. 272 (34): 21495–503. doi:10.1074/jbc.272.34.21495. PMID 9261168.
^ Hofmann I, Mertens C, Brettel M, Nimmrich V, Schnölzer M, Herrmann H (July 2000). "Interaction of plakophilins with desmoplakin and intermediate filament proteins: an in vitro analysis". J. Cell. Sci. 113 ( Pt 13): 2471–83. PMID 10852826.
^ Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ (March 2002). "Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling". J. Biol. Chem. 277 (12): 10512–22. doi:10.1074/jbc.M108765200. PMID 11790773.
^ Kowalczyk AP, Navarro P, Dejana E, Bornslaeger EA, Green KJ, Kopp DS et al. (October 1998). "VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions". J. Cell. Sci. 111 ( Pt 20): 3045–57. PMID 9739078.
^ Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM et al. (November 1997). "The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes". J. Cell Biol. 139 (3): 773–84. doi:10.1083/jcb.139.3.773. PMC 2141713. PMID 9348293.

External links

GeneReviews/NCBI/NIH/UW entry on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
OMIM entries on Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
Desmoplakins at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 腫瘍随伴性天疱瘡 paraneoplastic pemphigus
2. 不整脈原性右室心筋症：解剖学、組織学、病因、および遺伝学 arrhythmogenic right ventricular cardiomyopathy anatomy histology pathogenesis and genetics
3. 表皮水疱症の疫学、病因および臨床的特徴 epidemiology pathogenesis and clinical features of epidermolysis bullosa
4. 遺伝性の魚鱗癬の概要 overview of the inherited ichthyoses
5. 表皮水疱症の診断 diagnosis of epidermolysis bullosa

English Journal

Circulating plakin autoantibodies in a patient with erythema multiforme major: Are they pathogenic or a manifestation of epitope spreading?

Ellis E1, Sidhu S.Author information 1Department of Dermatology, Flinders Medical Centre, Bedford Park, South Australia, Australia.AbstractErythema multiforme is a well-recognised entity but its pathogenesis remains elusive. Theories hypothesise a cell-mediated immune pathogenesis, however recent case reports have observed autoantibodies to the plakin family of proteins, suggesting a role for the humoral immune system. We present a case of erythema multiforme major with circulating desmoplakin autoantibodies in a 36-year old woman who was previously diagnosed with pemphigoid gestationis. The close correlation between the concentration of these autoantibodies and the severity of clinical disease strongly suggests a pathogenic role in her disease. As previous case reports have proposed, these autoantibodies may be directly pathogenic. Alternatively, the epiphenomenon of epitope spreading must be considered in the subset of patients with erythema multiforme major.
The Australasian journal of dermatology.Australas J Dermatol.2014 Apr 1. doi: 10.1111/ajd.12162. [Epub ahead of print]
Erythema multiforme is a well-recognised entity but its pathogenesis remains elusive. Theories hypothesise a cell-mediated immune pathogenesis, however recent case reports have observed autoantibodies to the plakin family of proteins, suggesting a role for the humoral immune system. We present a cas
PMID 24689866

Plakins, a versatile family of cytolinkers: roles in skin integrity and in human diseases.

Bouameur JE1, Favre B2, Borradori L2.Author information 11] Departments of Dermatology and Clinical Research, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland [2] Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.2Departments of Dermatology and Clinical Research, Inselspital, Bern University Hospital, and University of Bern, Bern, Switzerland.AbstractThe plakin family consists of giant proteins involved in the cross-linking and organization of the cytoskeleton and adhesion complexes. They further modulate several fundamental biological processes, such as cell adhesion, migration, and polarization or signaling pathways. Inherited and acquired defects of plakins in humans and in animal models potentially lead to dramatic manifestations in the skin, striated muscles, and/or nervous system. These observations unequivocally demonstrate the key role of plakins in the maintenance of tissue integrity. Here we review the characteristics of the mammalian plakin members BPAG1 (bullous pemphigoid antigen 1), desmoplakin, plectin, envoplakin, epiplakin, MACF1 (microtubule-actin cross-linking factor 1), and periplakin, highlighting their role in skin homeostasis and diseases.
The Journal of investigative dermatology.J Invest Dermatol.2014 Apr;134(4):885-94. doi: 10.1038/jid.2013.498. Epub 2013 Dec 19.
The plakin family consists of giant proteins involved in the cross-linking and organization of the cytoskeleton and adhesion complexes. They further modulate several fundamental biological processes, such as cell adhesion, migration, and polarization or signaling pathways. Inherited and acquired def
PMID 24352042

Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes.

Tucker DK1, Stahley SN1, Kowalczyk AP2.Author information 11] Department of Cell Biology, Emory University, Atlanta, Georgia, USA [2] Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University, Atlanta, Georgia, USA.21] Department of Cell Biology, Emory University, Atlanta, Georgia, USA [2] Department of Dermatology, Emory University, Atlanta, Georgia, USA [3] Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.AbstractPlakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion. Here, we report that enhanced expression of PKP-1 protects keratinocytes from PV IgG-induced loss of cell-cell adhesion. PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell-cell borders and prevents alterations in desmosome ultrastructure in keratinocytes treated with PV IgG. Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a manner dependent on the plakoglobin-binding domain of the Dsg3 tail. Furthermore, PKP-1 expression transforms desmosome adhesion from a calcium-dependent to a calcium-independent and hyperadhesive state. These results demonstrate that manipulating the expression of a single desmosomal plaque protein can block the pathogenic effects of PV IgG on keratinocyte adhesion.
The Journal of investigative dermatology.J Invest Dermatol.2014 Apr;134(4):1033-43. doi: 10.1038/jid.2013.401. Epub 2013 Sep 20.
Plakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion. He
PMID 24056861

Japanese Journal

Compound and Digenic Heterozygosity in Desmosome Genes as a Cause of Arrhythmogenic Right Ventricular Cardiomyopathy in Japanese Patients

NAKAJIMA Tadashi,KANEKO Yoshiaki,IRIE Tadanobu,TAKAHASHI Rieko,KATO Toshimitsu,IIJIMA Takafumi,ISO Tatsuya,KURABAYASHI Masahiko
Circulation journal : official journal of the Japanese Circulation Society 76(3), 737-743, 2012-02-25
… Genetic screening for major ARVC-causing genes (junction plakoglobin, desmoplakin, plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocollin-2) was performed. …
NAID 10030130444

A New Hypo/Oligodontia Syndrome : Carvajal/Naxos Syndrome Secondary to Desmoplakin-dominant Mutations

CHALABREYSSE L.,SENNI F.,BRUYERE P.,AIME B.,OLLAGNIER C.,BOZIO A.,BOUVAGNET P.
Journal of dental research 90(1), 58-64, 2011-01-01
NAID 10031010131

Novel Compound Heterozygosity in Desmoglein-2 Associated with Arrhythmogenic Right Ventricular Cardiomyopathy

Nakajima Tadashi,Kaneko Yoshiaki,Irie Tadanobu,Kato Toshimitsu,Iijima Takafumi,Takahashi Rieko,Iso Tatsuya,Kurabayashi Masahiko
Journal of Arrhythmia 27(Supplement), PE4_058-PE4_058, 2011
… Genetic screening of major ARVC-causing desmosome genes (junction plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2) identified 2 novel mutations, S194L and R292C, in desmoglein-2, which were not identified in 160 control alleles. …
NAID 130002129707

Related Pictures

★リンクテーブル★

リンク元	「腫瘍随伴性天疱瘡」「デスモプラキン」「付着板」

「腫瘍随伴性天疱瘡」

Desmoplakin
	PDB rendering based on 1lm5.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1LM5, 1LM7, 3R6N
Identifiers
Symbols	DSP ; DCWHKTA; DP; DPI; DPII
External IDs	OMIM: 125647 MGI: 109611 HomoloGene: 37922 GeneCards: DSP Gene
Gene ontology
Molecular function	• protein kinase C binding; • structural molecule activity; • structural constituent of cytoskeleton; • protein binding; • protein binding, bridging; • poly(A) RNA binding; • cell adhesion molecule binding; • cell adhesive protein binding involved in bundle of His cell-Purkinje myocyte communication; • scaffold protein binding;
Cellular component	• cornified envelope; • nucleus; • cytoplasm; • intermediate filament; • plasma membrane; • fascia adherens; • intercalated disc; • basolateral plasma membrane; • desmosome; • extracellular exosome;
Biological process	• desmosome organization; • ventricular compact myocardium morphogenesis; • apoptotic process; • cellular component disassembly involved in execution phase of apoptosis; • epidermis development; • programmed cell death; • peptide cross-linking; • keratinocyte differentiation; • adherens junction organization; • wound healing; • intermediate filament organization; • protein localization to adherens junction; • bundle of His cell-Purkinje myocyte adhesion involved in cell communication; • regulation of heart rate by cardiac conduction; • regulation of ventricular cardiac muscle cell action potential;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
	v; t; e;

　　[★]

英: paraneoplastic pemphigus
関: 天疱瘡

概念

良性または悪性新生物(顕性 or 不顕性(occult))に合併して出現し、びらん形成を主体とした重篤な粘膜病変と多彩な皮膚病変を呈する。
典型的にはリンパ網内系悪性腫瘍(lymphoreticular malignancy)を合併する；ホジキンリンパ腫、慢性リンパ性白血病、キャッスルマン病、胸腺腫、マクログロブリン血症。
デスモグレインやプラキンファミリー分子に対する自己抗体が原因とされる。

病因

デスモグレイン1、デスモグレイン3(Dsg1、Dsg3)、デスモプラキン desmoplakin(plakin proteins)に対する自己抗体の産生による

症状

重度の皮膚粘膜病変：眼病変(偽膜性角結膜炎)や口腔内水疱を伴う。
皮膚病変は多型性紅斑、水疱性類天疱瘡、扁平苔癬に似ている

診断

(腫瘍が見つかっていない場合)重症の口腔内水疱病変と非典型的な皮膚所見から疑い、腫瘍の検索を行う。

治療

原疾患の治療
尋常性天疱と同じ治療；第一選択全身グルココルチコイド療法；シクロスポリンやシクロホスファミドと組み合わせて使われるうる。

予後

進行性であり、悪性腫瘍合併しているときは二年間以内に致命的な結末をもたらす。悪性新生物に合併しているときは原疾患の治療を改善しないが、良性新生物の場合は原疾患の治療により皮膚病変が治癒する。

参考

Beth G Goldstein MD et al.; Pemphigus; UpToDate; review version 18.2

「デスモプラキン」

　　[★]

英: desmoplakin
関: 腫瘍随伴性天疱瘡、線状掌蹠角化症

概念

デスモソームの接着板に存在する細胞内蛋白
細胞内でケラチンに結合、またadhesion proteinと結合している。adhesion proteinは細胞膜を貫通し、細胞間の接着に関わっている。

参考

http://cshperspectives.cshlp.org/content/1/2/a002543.full

http://www.medizin.uni-halle.de/pathobiochemie/index.php?id=307

「付着板」

　　[★]

英: (皮膚)attachment plaque

皮膚科学

NDE.6
デスモソームは付着板と呼ばれる細胞内の部位と細胞を貫通して細胞間の接着を担う部位からなる
デスモソーム

付着板

デスモプラキン desmoplakin
プラコフィリン [[]]
パコグロビン pakoglobin (HIS.85)

[pmid1889810-1] Arnemann J, Spurr NK, Wheeler GN, Parker AE, Buxton RS (October 1991). "Chromosomal assignment of the human genes coding for the major proteins of the desmosome junction, desmoglein DGI (DSG), desmocollins DGII/III (DSC), desmoplakins DPI/II (DSP), and plakoglobin DPIII (JUP)". Genomics 10 (3): 640–5. doi:10.1016/0888-7543(91)90446-L. PMID 1889810.

[entrez-2] "Entrez Gene: DSP desmoplakin".

[pmid8769422-3] Bornslaeger EA, Corcoran CM, Stappenbeck TS, Green KJ (August 1996). "Breaking the connection: displacement of the desmosomal plaque protein desmoplakin from cell-cell interfaces disrupts anchorage of intermediate filament bundles and alters intercellular junction assembly". J. Cell Biol. 134 (4): 985–1001. doi:10.1083/jcb.134.4.985. PMC 2120955. PMID 8769422.

[4] "Protein sequence of human desmoplakin (Uniprot ID: P15924)". Cardiac Organellar Protein Atlas Knowledgabase (COPaKB). Retrieved 26 June 2015.

[5] "Protein sequence of human desmoplakin (Uniprot ID: P15924-2)". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Retrieved 26 June 2015.

[6] Al-Jassar C, Bikker H, Overduin M, Chidgey M (Nov 2013). "Mechanistic basis of desmosome-targeted diseases". Journal of Molecular Biology 425 (21): 4006–22. doi:10.1016/j.jmb.2013.07.035. PMID 23911551.

[ReferenceA-7] Green KJ, Parry DA, Steinert PM, Virata ML, Wagner RM, Angst BD et al. (Feb 1990). "Structure of the human desmoplakins. Implications for function in the desmosomal plaque". The Journal of Biological Chemistry 265 (5): 2603–12. PMID 1689290.

[8] Jefferson JJ, Ciatto C, Shapiro L, Liem RK (Feb 2007). "Structural analysis of the plakin domain of bullous pemphigoid antigen1 (BPAG1) suggests that plakins are members of the spectrin superfamily". Journal of Molecular Biology 366 (1): 244–57. doi:10.1016/j.jmb.2006.11.036. PMID 17161423.

[9] Choi HJ, Weis WI (2011). "Crystal structure of a rigid four-spectrin-repeat fragment of the human desmoplakin plakin domain". J. Mol. Biol. 409 (5): 800–12. doi:10.1016/j.jmb.2011.04.046. PMC 3107870. PMID 21536047.

[10] Al-Jassar C, Knowles T, Jeeves M, Kami K, Behr E, Bikker H et al. (2011). "The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations". J. Mol. Biol. 411 (5): 1049–61. doi:10.1016/j.jmb.2011.06.047. PMID 21756917.

[11] Choi HJ, Park-Snyder S, Pascoe LT, Green KJ, Weis WI (Aug 2002). "Structures of two intermediate filament-binding fragments of desmoplakin reveal a unique repeat motif structure". Nature Structural Biology 9 (8): 612–20. doi:10.1038/nsb818. PMID 12101406.

[12] Stappenbeck TS, Bornslaeger EA, Corcoran CM, Luu HH, Virata ML, Green KJ (Nov 1993). "Functional analysis of desmoplakin domains: specification of the interaction with keratin versus vimentin intermediate filament networks". The Journal of Cell Biology 123 (3): 691–705. PMID 7693716.

[13] Stappenbeck TS, Lamb JA, Corcoran CM, Green KJ (Nov 1994). "Phosphorylation of the desmoplakin COOH terminus negatively regulates its interaction with keratin intermediate filament networks". The Journal of Biological Chemistry 269 (47): 29351–4. PMID 7525582.

[Garrod_D_2007-14] Garrod D, Chidgey M (Mar 2008). "Desmosome structure, composition and function". Biochimica Et Biophysica Acta 1778 (3): 572–87. doi:10.1016/j.bbamem.2007.07.014. PMID 17854763.

[15] Kartenbeck J, Schwechheimer K, Moll R, Franke WW (Mar 1984). "Attachment of vimentin filaments to desmosomal plaques in human meningiomal cells and arachnoidal tissue". The Journal of Cell Biology 98 (3): 1072–81. PMID 6365927.

[16] Kartenbeck J, Franke WW, Moser JG, Stoffels U (1983). "Specific attachment of desmin filaments to desmosomal plaques in cardiac myocytes". The EMBO Journal 2 (5): 735–42. PMID 6416832.

[17] Gallicano GI, Kouklis P, Bauer C, Yin M, Vasioukhin V, Degenstein L et al. (Dec 1998). "Desmoplakin is required early in development for assembly of desmosomes and cytoskeletal linkage". The Journal of Cell Biology 143 (7): 2009–22. PMID 9864371.

[ReferenceB-18] Yang Z, Bowles NE, Scherer SE, Taylor MD, Kearney DL, Ge S et al. (Sep 2006). "Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular dysplasia/cardiomyopathy". Circulation Research 99 (6): 646–55. doi:10.1161/01.RES.0000241482.19382.c6. PMID 16917092.

[19] Awad MM, Calkins H, Judge DP (May 2008). "Mechanisms of disease: molecular genetics of arrhythmogenic right ventricular dysplasia/cardiomyopathy". Nature Clinical Practice. Cardiovascular Medicine 5 (5): 258–67. doi:10.1038/ncpcardio1182. PMID 18382419.

[ReferenceC-20] Norgett EE, Hatsell SJ, Carvajal-Huerta L, Cabezas JC, Common J, Purkis PE et al. (Nov 2000). "Recessive mutation in desmoplakin disrupts desmoplakin-intermediate filament interactions and causes dilated cardiomyopathy, woolly hair and keratoderma". Human Molecular Genetics 9 (18): 2761–6. PMID 11063735.

[21] Carvajal-Huerta L (Sep 1998). "Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy". Journal of the American Academy of Dermatology 39 (3): 418–21. PMID 9738775.

[22] Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V et al. (Nov 2002). "Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy". American Journal of Human Genetics 71 (5): 1200–6. doi:10.1086/344208. PMID 12373648.

[23] Alcalai R, Metzger S, Rosenheck S, Meiner V, Chajek-Shaul T (Jul 2003). "A recessive mutation in desmoplakin causes arrhythmogenic right ventricular dysplasia, skin disorder, and woolly hair". Journal of the American College of Cardiology 42 (2): 319–27. PMID 12875771.

[Uzumcu_A_2005-24] Uzumcu A, Norgett EE, Dindar A, Uyguner O, Nisli K, Kayserili H et al. (Feb 2006). "Loss of desmoplakin isoform I causes early onset cardiomyopathy and heart failure in a Naxos-like syndrome". Journal of Medical Genetics 43 (2): e5. doi:10.1136/jmg.2005.032904. PMID 16467215.

[25] van der Zwaag PA, Jongbloed JD, van den Berg MP, van der Smagt JJ, Jongbloed R, Bikker H et al. (Sep 2009). "A genetic variants database for arrhythmogenic right ventricular dysplasia/cardiomyopathy". Human Mutation 30 (9): 1278–83. doi:10.1002/humu.21064. PMID 19569224.

[26] Al-Jassar C, Knowles T, Jeeves M, Kami K, Behr E, Bikker H et al. (Sep 2011). "The nonlinear structure of the desmoplakin plakin domain and the effects of cardiomyopathy-linked mutations". Journal of Molecular Biology 411 (5): 1049–61. doi:10.1016/j.jmb.2011.06.047. PMID 21756917.

[27] Armstrong DK, McKenna KE, Purkis PE, Green KJ, Eady RA, Leigh IM et al. (Jan 1999). "Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma". Human Molecular Genetics 8 (1): 143–8. PMID 9887343.

[28] Whittock NV, Ashton GH, Dopping-Hepenstal PJ, Gratian MJ, Keane FM, Eady RA et al. (Dec 1999). "Striate palmoplantar keratoderma resulting from desmoplakin haploinsufficiency". The Journal of Investigative Dermatology 113 (6): 940–6. doi:10.1046/j.1523-1747.1999.00783.x. PMID 10594734.

[29] Whittock NV, Wan H, Morley SM, Garzon MC, Kristal L, Hyde P et al. (Feb 2002). "Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome". The Journal of Investigative Dermatology 118 (2): 232–8. doi:10.1046/j.0022-202x.2001.01664.x. PMID 11841538.

[30] Carvajal-Huerta L (Sep 1998). "Epidermolytic palmoplantar keratoderma with woolly hair and dilated cardiomyopathy". Journal of the American Academy of Dermatology 39 (3): 418–21. PMID 9738775.

[31] Jonkman MF, Pasmooij AM, Pasmans SG, van den Berg MP, Ter Horst HJ, Timmer A et al. (Oct 2005). "Loss of desmoplakin tail causes lethal acantholytic epidermolysis bullosa". American Journal of Human Genetics 77 (4): 653–60. doi:10.1086/496901. PMID 16175511.

[32] McGrath JA, Bolling MC, Jonkman MF (Jan 2010). "Lethal acantholytic epidermolysis bullosa". Dermatologic Clinics 28 (1): 131–5. doi:10.1016/j.det.2009.10.015. PMID 19945626.

[33] Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M et al. (Dec 1990). "Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia". The New England Journal of Medicine 323 (25): 1729–35. doi:10.1056/NEJM199012203232503. PMID 2247105.

[34] Oursler JR, Labib RS, Ariss-Abdo L, Burke T, O'Keefe EJ, Anhalt GJ (Jun 1992). "Human autoantibodies against desmoplakins in paraneoplastic pemphigus". The Journal of Clinical Investigation 89 (6): 1775–82. doi:10.1172/JCI115781. PMID 1601988.

[35] Papagerakis S, Shabana AH, Pollock BH, Papagerakis P, Depondt J, Berdal A (Sep 2009). "Altered desmoplakin expression at transcriptional and protein levels provides prognostic information in human oropharyngeal cancer". Human Pathology 40 (9): 1320–9. doi:10.1016/j.humpath.2009.02.002. PMID 19386346.

[36] Pang H, Rowan BG, Al-Dhaheri M, Faber LE (2004). "Epidermal growth factor suppresses induction by progestin of the adhesion protein desmoplakin in T47D breast cancer cells". Breast Cancer Research 6 (3): R239–45. doi:10.1186/bcr780. PMID 15084247.

[pmid9261168-37] Meng JJ, Bornslaeger EA, Green KJ, Steinert PM, Ip W (August 1997). "Two-hybrid analysis reveals fundamental differences in direct interactions between desmoplakin and cell type-specific intermediate filaments". J. Biol. Chem. 272 (34): 21495–503. doi:10.1074/jbc.272.34.21495. PMID 9261168.

[pmid10852826-38] Hofmann I, Mertens C, Brettel M, Nimmrich V, Schnölzer M, Herrmann H (July 2000). "Interaction of plakophilins with desmoplakin and intermediate filament proteins: an in vitro analysis". J. Cell. Sci. 113 ( Pt 13): 2471–83. PMID 10852826.

[pmid11790773-39] Chen X, Bonne S, Hatzfeld M, van Roy F, Green KJ (March 2002). "Protein binding and functional characterization of plakophilin 2. Evidence for its diverse roles in desmosomes and beta -catenin signaling". J. Biol. Chem. 277 (12): 10512–22. doi:10.1074/jbc.M108765200. PMID 11790773.

[pmid9739078-40] Kowalczyk AP, Navarro P, Dejana E, Bornslaeger EA, Green KJ, Kopp DS et al. (October 1998). "VE-cadherin and desmoplakin are assembled into dermal microvascular endothelial intercellular junctions: a pivotal role for plakoglobin in the recruitment of desmoplakin to intercellular junctions". J. Cell. Sci. 111 ( Pt 20): 3045–57. PMID 9739078.

[pmid9348293-41] Kowalczyk AP, Bornslaeger EA, Borgwardt JE, Palka HL, Dhaliwal AS, Corcoran CM et al. (November 1997). "The amino-terminal domain of desmoplakin binds to plakoglobin and clusters desmosomal cadherin-plakoglobin complexes". J. Cell Biol. 139 (3): 773–84. doi:10.1083/jcb.139.3.773. PMC 2141713. PMID 9348293.

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案内

desmoplakin