• Dignya Desai
  • Vaibhav Modi
  • Manali Datta Amity University Rajasthan


Objective: Acral peeling skin syndrome (APSS), a rare genetic disorder, indicated by the continuous blistering and shedding of the outer epidermal
layers. Transglutaminase 5 (TGM5), a calcium-dependent TGM, present in the epidermis has been implicated as the cause of APSS. An attempt has
been made to compare in silico the wild and mutant form of TGM5 and its implication on its interaction with involucrin (IVL).
Methods: Comparative modeling was performed using MAESTRO for proteins TGM5 and IVL using templates from the protein databank. Generated
model was later refined using side chain refinement and loop refinement. Three-dimensional (3D) structure of TGM5 and IVL was analyzed in
PROCHECK, VERIFY3D, and ERRAT was used to assess the reliability of the 3D model. IMPACT package from Schrödinger was used to generate a
binding site for calcium ion which is essential for functioning of protein. Energy minimization for the modelled structures was performed using
IMPACT module of Schrodinger. Subsequently, wild type and mutated models of TGM5 was used for performing docking studies with IVL.
Results: The structures for TGM5 and IVL were modeled and energy minimized using Schrödinger suite. Conserved calcium binding domain formed
by three asparagine residues (N224, N226 and N229) and alanine (A221) corresponding to TGM3 was found in TGM5 at positions 226, 229, 231,
and 234. Identification of probable active site for TGM5 was predicted using SiteMap program in Schrödinger. 17 cysteine residues are present in
wild type structure of TGM5 and in mutated form G113C, the probability of forming an extra disulfide increases. With the mutation occurring at
113 position formation of disulfide bond between C113 and Cys306 increases manifold. This hypothesis was confirmed by the fact that root-meansquare
distance value
minimized mutated
on aligning all
be 0.141 indicating

change of overall
of protein.
Conclusion: The mutation G113C is increasing the dynamic nature of the protein to increase as the probability of the formation of disulfide bond
Keywords: Skin, Acral peeling skin syndrome, Glutaminase, Involucrin, Mutation, Interaction.

Author Biography

Manali Datta, Amity University Rajasthan

Amity Institute of Biotechnology

Assistant Proffessor and Program co-ordinator


1. Kiritsi D, Cosgarea I, Franzke CW, Schumann H, Oji V, Kohlhase J,
et al. Acral peeling skin syndrome with TGM5 gene mutations may
resemble epidermolysis bullosa simplex in young individuals. J Invest
Dermatol 2010;130(6):1741-6.
2. Kharfi M, El Fekih N, Ammar D, Jaafoura H, Schwonbeck S, van
Steensel MA, et al. A missense mutation in TGM5 causes acral
peeling skin syndrome in a Tunisian family. J Invest Dermatol
3. Cassidy AJ, van Steensel MA, Steijlen PM, van Geel M, van der
Velden J, Morley SM, et al. A homozygous missense mutation in
TGM5 abolishes epidermal transglutaminase 5 activity and causes acral
peeling skin syndrome. Am J Hum Genet 2005;77(6):909-17.
4. Pietroni V, Di Giorgi S, Paradisi A, Ahvazi B, Candi E, Melino G.
Inactive and highly active, proteolytically processed transglutaminase-5
in epithelial cells. J Invest Dermatol 2008;128(12):2760-6.
5. Pigors M, Kiritsi D, Cobzaru C, Schwieger-Briel A, Suárez J, Faletra F,
et al. TGM5 mutations impact epidermal differentiation in acral peeling
skin syndrome. J Invest Dermatol 2012;132(10):2422-9.
6. Tong L, Corrales RM, Chen Z, Villarreal AL, De Paiva CS, Beuerman R,
et al. Expression and regulation of cornified envelope proteins in human
corneal epithelium. Invest Ophthalmol Vis Sci 2006;47(5):1938-46.
7. Candi E, Oddi S, Terrinoni A, Paradisi A, Ranalli M, Finazzi-Agró A,
et al. Transglutaminase 5 cross-links loricrin, involucrin, and small
proline-rich proteins in vitro. J Biol Chem 2001;276(37):35014-23.
8. Simon M, Green H. The glutamine residues reactive in
transglutaminase-catalyzed cross-linking of involucrin. J Biol Chem
9. Bragulla HH, Homberger DG. Structure and functions of keratin
proteins in simple, stratified, keratinized and cornified epithelia. J Anat
10. Suite 2012: Maestro, Version 9.3. Schrödinger. New York, NY: LLC;
2012. Suite 2011: Maestro, Version 9.2. Schrödinger, New York, NY:
LLC; 2011.
11. Jacobson MP, Pincus DL, Rapp CS, Day TJ, Honig B, Shaw DE, et al.
A hierarchical approach to all-atom protein loop prediction. Proteins
12. Jacobson MP, Friesner RA, Xiang Z, Honig B. On the role of the crystal
environment in determining protein side-chain conformations. J Mol
Biol 2002;320(3):597-608.
13. Laskowski RA, MacArthur MW, Thornton JM. PROCHECK:
Validation of protein structure coordinates, in international tables of
crystallography. In: Rossmann MG, Arnold E, editors. Crystallography
of Biological Macromolecules. Volume F. Netherlands, Dordrecht:
Kluwer Academic Publishers; 2001. p. 722-5.
14. Morris AL, MacArthur MW, Hutchinson EG, Thornton JM.
Stereochemical quality of protein structure coordinates. Proteins
15. Eisenberg D, Lüthy R, Bowie JU. VERIFY3D: Assessment of
protein models with three-dimensional profiles. Methods Enzymol
16. Colovos C, Yeates TO. Verification of protein structures: Patterns of
nonbonded atomic interactions. Protein Sci 1993;2(9):1511-9.
17. Sippl MJ. Recognition of errors in three-dimensional structures of
proteins. Proteins 1993;17(4):355-62.
18. Wiederstein M, Sippl MJ. ProSA-web: Interactive web service for
the recognition of errors in three-dimensional structures of proteins.
Nucleic Acids Res 2007;35:W407-10.
19. Huang YC, Wang TW, Sun JS, Lin FH. Effect of calcium ion
concentration on keratinocyte behaviors in the defined media. Biomed
Eng Appl Basis Commun 2006;18:37-41.
20. Numaga-Tomita T, Putney JW. Role of STIM1 - And Orai1-mediated
Ca2 entry in Ca2 - Induced epidermal keratinocyte differentiation.
J Cell Sci 2013;126:605-12.
21. Klöck C, Diraimondo TR, Khosla C. Role of transglutaminase 2 in
celiac disease pathogenesis. Semin Immunopathol 2012;34(4):513-22.
22. Ahvazi B, Boeshans KM, Idler W, Baxa U, Steinert PM. Roles of
calcium ions in the activation and activity of the transglutaminase
3 enzyme. J Biol Chem 2003;278(26):23834-41.
23. Pierce BG, Wiehe K, Hwang H, Kim BH, Vreven T, Weng Z. ZDOCK
server: Interactive docking prediction of protein-protein complexes and
symmetric multimers. Bioinformatics 2014;30(12):1771-3.
24. Hitomi K, Kojima S, Fesus L, editors. Transglutaminases Multiple
Functional Modifiers and Targets for New Drug Discovery. New York:
Springer Tokyo Heidelberg; 2015.
25. Pedersen LC, Yee VC, Bishop PD, Le Trong I, Teller DC, Stenkamp
RE. Transglutaminase factor XIII uses proteinase-like catalytic triad to
crosslink macromolecules. Protein Sci 1994;3(7):1131-5.
26. Trivedi MV, Laurence JS, Siahaan TJ. The role of thiols and disulfides
in protein chemical and physical stability. Curr Protein Pept Sci
27. Kavaklieva S, Yordanova I, Bruckner-Tuderman L, Has C. Acral
peeling skin syndrome resembling epidermolysis bullosa simplex in a
10-month-old boy. Case Rep Dermatol 2013;5(2):210-4.
28. Mukherjee J, Gupta MN. Increasing importance of protein flexibility in
designing biocatalytic processes. Biotechnol Rep 2015;6:119-23.
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How to Cite
Desai, D., V. Modi, and M. Datta. “IN SILICO ANALYSIS OF ACRAL PEELING SKIN SYNDROME: A PROTEOMIC APPROACH”. Asian Journal of Pharmaceutical and Clinical Research, Vol. 9, no. 4, July 2016, pp. 316-9,
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