Journal of Molecular Modeling

, Volume 13, Issue 1, pp 233–246

A three-dimensional model of the human transglutaminase 1: insights into the understanding of lamellar ichthyosis

  • Karen M. Boeshans
  • Timothy C. Mueser
  • Bijan Ahvazi
Original Paper


The stratum corneum, the outer layer of the epidermis, serves as a protective barrier to isolate the skin from the external environment. Keratinocyte transglutaminase 1 (TGase 1) catalyzes amide crosslinking between glutamine and lysine residues on precursor proteins forming the impermeable layers of the epidermal cell envelopes (CE), the highly insoluble membranous structures of the stratum corneum. Patients with the autosomal recessive skin disorder lamellar ichthyosis (LI) appear to have deficient cross-linking of the cell envelope due to mutations identified in TGase 1, linking this enzyme to LI. In the absence of a crystal structure, molecular modeling was used to generate the structure of TGase 1. We have mapped the known mutations of TGase 1 from our survey obtained from a search of PubMed and successfully predicted the impact of these mutations on LI. Furthermore, we have identified Ca2+ binding sites and propose that Ca2+ induces a cis to trans isomerization in residues near the active site as part of the enzyme transamidation activation. Docking experiments suggest that substrate binding subsequently induces the reverse cis to trans isomerization, which may be a significant part of the catalytic process. These results give an interpretation at the molecular level of previously reported mutations and lead to further insights into the structural model of TGase 1, providing a new basis for understanding LI.


Ribbon image of the model of the human TGase 1 structure. The side chains of residues reported to be mutated in patients with LI (34 amino acid mutation sites) are shown as spheres.


Keratinocyte transglutaminase 1 Lamellar ichthyosis Mutations Metal ions Isomerization Molecular modeling 


TGase 1

keratinocyte transglutaminase 1


lamellar ichthyosis


guanosine 5′-triphosphate


root mean square deviation




ethylenediaminetetraacetic acid


trichloroacetic acid


cell envelope


small proline-rich proteins


structurally conserved regions


structurally variable regions


computer aided molecular design


cis to trans isomerization


  1. 1.
    Anton-Lamprecht I (1992) The skin. In: Papadimitriou JM, Henderson DW, Spagnolo DV (eds) Diagnostic ultrastructure of non-neoplastic diseases. Edinburgh, Churchill and Livingstone, pp 459–550Google Scholar
  2. 2.
    Williams ML, Elias PM (1985) Arch Dermatol 121:477–488CrossRefGoogle Scholar
  3. 3.
    Russell LJ, DiGiovanna JJ, Rogers GR, Steinert PM, Hashem N, Compton JG, Bale SJ (1995) Nat Genet 9:279–283CrossRefGoogle Scholar
  4. 4.
    Russell LJ, DiGiovanna JJ, Hashem N, Compton JG, Bale SJ (1994) Am J Hum Genet 55:114–1152Google Scholar
  5. 5.
    Laiho E, Niemi KM, Ignatius J, Kere J, Palotie A, Saarialho-Kere U (1999) Eur J Hum Genet 7:625–632CrossRefGoogle Scholar
  6. 6.
    Laiho E, Ignatius J, Mikkola H, Yee VC, Teller DC, Niemi KM, Saarialho-Kere U, Kere J, Palote A (1997) Am J Hum Genet 61:529–538Google Scholar
  7. 7.
    Williams M, Elias PM (2000) Curr Probl Dermatol 12:170–176CrossRefGoogle Scholar
  8. 8.
    Huber M, Rettler I, Bernasconi K, Frenk E, Lavrijsen SP, Ponec M, Bon A, Lautenschlager S, Schorderet DF, Hohl D (1995) Science 267:525–528CrossRefGoogle Scholar
  9. 9.
    Choate KA, Williams ML, Khavari PA (1998) J Invest Dermatol 110:8–12CrossRefGoogle Scholar
  10. 10.
    Liu S, Cerione RA, Clardy J (2002) Proc Natl Acad Sci 99:2743–2747CrossRefGoogle Scholar
  11. 11.
    Ahvazi B, Boeshans KM, Idler W, Baxa U, Steinert PM, Rastinejad F (2004) J Biol Chem 279:7180–7192CrossRefGoogle Scholar
  12. 12.
    Kim IG, McBride W, Wang M, Kim SY, Idler WW, Steinert PM (1992) J Biol Chem 267:7710–7717Google Scholar
  13. 13.
    Steinert PM, Kim SY, Chung SI, Marekov LN (1996) J Biol Chem 271:26242–26250CrossRefGoogle Scholar
  14. 14.
    Nemes Z, Marekov LN, Fesüs L, Steinert PM (1996) Proc Natl Acad Sci 96:8402–8407CrossRefGoogle Scholar
  15. 15.
    Phillips MA, Stewart BE, Qin Q, Chakravarty R, Floyd EE, Jetten AM, Rice RH (1990) Proc Natl Acad Sci 87:9333–9337CrossRefGoogle Scholar
  16. 16.
    Phillips MA, Qin Q, Mehrpouyan M, Rice RH (19923) Biochemistry 32:11057–11063CrossRefGoogle Scholar
  17. 17.
    Pilgram GSK, Vissers DCJ, van der Meulen H, Pavel S, Lavrijsen SPM, Bouwstra JA, Koerten HK (2001) J Invest Dermatol 117:710–717CrossRefGoogle Scholar
  18. 18.
    Hennies HC, Kuster W, Wiebe V, Krebsova A, Reis A (1998) Am J Hum Genet 62:1052–1061CrossRefGoogle Scholar
  19. 19.
    Gish W (1996–2002)
  20. 20.
    Godzik A, Kolinski A, Skolnick J (1992) J Mol Biol 227:227–238CrossRefGoogle Scholar
  21. 21.
    McGuffin LJ, Bryson K, Jones DT (2000) Bioinformatics 16:404–405CrossRefGoogle Scholar
  22. 22.
    Lüthy R, Bowie JU, Eisenberg D (1992) Nature 356:83–85CrossRefGoogle Scholar
  23. 23.
    Sabnis Y, Desai PV, Rosenthal PJ, Avery MA (2003) Prot Sci 12:501–509CrossRefGoogle Scholar
  24. 24.
    Jones TA, Thirup S (1986) EMBO J 5:819–822Google Scholar
  25. 25.
    Stouten PFW, Froemmel C, Nakamura H, Sander C (1993) Mol Simul 10:97–120Google Scholar
  26. 26.
    Greengard L, Rokhlin VI (1987) J Comp Phys 73:325–348CrossRefGoogle Scholar
  27. 27.
    Verlet L (1967) Phys Rev 159:98–103CrossRefGoogle Scholar
  28. 28.
    Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1992) J Appl Cryst 26:283–291CrossRefGoogle Scholar
  29. 29.
    Merritt EA, Bacon DJ (1997) Method Enzymol 277:505–525CrossRefGoogle Scholar
  30. 30.
    Kraulis PJ (1991) J Appl Cryst 24:946–950CrossRefGoogle Scholar
  31. 31.
    SYBYL 6.7 (1995) Tripos Assoc. Inc., St. Louis, MOGoogle Scholar
  32. 32.
    Ahvazi B, Kim HC, Kee SH, Nemes Z, Steinert PM (2002) EMBO J 21:2055–2067CrossRefGoogle Scholar
  33. 33.
    Ahvazi B, Boeshans KM, Jang S-I, Kalinin P, Steinert PM (2002) Minerva Biotecnol 14:165–169Google Scholar
  34. 34.
    Ahvazi B, Boeshans KM, Idler W, Baxa U, Steinert PM (2003) J Biol Chem 278:23834–23841CrossRefGoogle Scholar
  35. 35.
    Ahvazi B, Boeshans KM, Steinert PM (2004) J Biol Chem 279:26716–26725CrossRefGoogle Scholar
  36. 36.
    Menon GK, Elias PM (1991) Arch Dermatol 127:57–63CrossRefGoogle Scholar
  37. 37.
    Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yuspa SH (1980) Cell 19:245–254CrossRefGoogle Scholar
  38. 38.
    Ahvazi B, Steinert PM (2003) Exp Mol Med 35:228–242Google Scholar
  39. 39.
    Ahvazi B, Boeshans KM, Rastinejad F (2004) J Struct Biol 147:200–207CrossRefGoogle Scholar
  40. 40.
    Weiss MS, Jabs A, Hilgenfeld R (1998) Nat Struct Biol 5:676CrossRefGoogle Scholar
  41. 41.
    Jabs A, Weiss MS, Hilgenfeld R (1999) J Mol Biol 286:291–304CrossRefGoogle Scholar
  42. 42.
    Stoddard BL, Pietrokovski S (1998) Nat Struct Biol 5:3–5CrossRefGoogle Scholar
  43. 43.
    Folkers G (1998) In: Codding PW (ed) Structure-based drug design: experimental and computational approaches. Kluwer Academic Publisher, Norwell, MA, pp 271–283Google Scholar
  44. 44.
    Candi E, Tarcsa E, Idler WW, Kartasova T, Marekov LN, Steinert PM (1999) J Biol Chem 274:7226–7237CrossRefGoogle Scholar
  45. 45.
    Ludwig M, Pattridge K, Metzger A, Dixon M, Eren M, Feng Y, Swenson R (1997) Biochemistry 36:1259–1280CrossRefGoogle Scholar
  46. 46.
    Heroux A, White E, Ross L, Davis R, Borhani D (1999) Biochemistry 38:14495–14506CrossRefGoogle Scholar
  47. 47.
    Stewart D, Sarkar A, Wampler J (1990) J Mol Biol 214:253–260CrossRefGoogle Scholar
  48. 48.
    Lin LN, Brandts JF (1993) Biochemistry 22:564–573CrossRefGoogle Scholar
  49. 49.
    Scherer G, Kramer M, Schutkowski M, Reimer U, Fischer G (1998) J Am Chem Soc 120:5568–5579CrossRefGoogle Scholar
  50. 50.
    Schiene-Fischer C, Fischer G (2001) J Am Chem Soc 123:6227–6231CrossRefGoogle Scholar
  51. 51.
    Reimer U, Fischer G (2002) Biophys Chemist 96:203–212CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Karen M. Boeshans
    • 1
  • Timothy C. Mueser
    • 2
  • Bijan Ahvazi
    • 1
    • 3
  1. 1.X-ray Crystallography Facility/Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Department of ChemistryUniversity of ToledoToledoUSA
  3. 3.X-ray Crystallography FacilityNIAMSBethesdaUSA

Personalised recommendations