Skip to main content
SpringerLink
Log in

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

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

TGase 1:

keratinocyte transglutaminase 1

LI:

lamellar ichthyosis

GTP:

guanosine 5′-triphosphate

RMSD:

root mean square deviation

DTT:

1,4-dithio-dl-threitol

EDTA:

ethylenediaminetetraacetic acid

TCA:

trichloroacetic acid

CE:

cell envelope

SPRs:

small proline-rich proteins

SCRs:

structurally conserved regions

SVRs:

structurally variable regions

MolCad:

computer aided molecular design

CTI:

cis to trans isomerization

References

  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 459–550

    Google Scholar 

  2. Williams ML, Elias PM (1985) Arch Dermatol 121:477–488

    Article  CAS  Google Scholar 

  3. Russell LJ, DiGiovanna JJ, Rogers GR, Steinert PM, Hashem N, Compton JG, Bale SJ (1995) Nat Genet 9:279–283

    Article  CAS  Google Scholar 

  4. Russell LJ, DiGiovanna JJ, Hashem N, Compton JG, Bale SJ (1994) Am J Hum Genet 55:114–1152

    Google Scholar 

  5. Laiho E, Niemi KM, Ignatius J, Kere J, Palotie A, Saarialho-Kere U (1999) Eur J Hum Genet 7:625–632

    Article  CAS  Google Scholar 

  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 61:529–538

    CAS  Google Scholar 

  7. Williams M, Elias PM (2000) Curr Probl Dermatol 12:170–176

    Article  Google Scholar 

  8. Huber M, Rettler I, Bernasconi K, Frenk E, Lavrijsen SP, Ponec M, Bon A, Lautenschlager S, Schorderet DF, Hohl D (1995) Science 267:525–528

    Article  CAS  Google Scholar 

  9. Choate KA, Williams ML, Khavari PA (1998) J Invest Dermatol 110:8–12

    Article  CAS  Google Scholar 

  10. Liu S, Cerione RA, Clardy J (2002) Proc Natl Acad Sci 99:2743–2747

    Article  CAS  Google Scholar 

  11. Ahvazi B, Boeshans KM, Idler W, Baxa U, Steinert PM, Rastinejad F (2004) J Biol Chem 279:7180–7192

    Article  CAS  Google Scholar 

  12. Kim IG, McBride W, Wang M, Kim SY, Idler WW, Steinert PM (1992) J Biol Chem 267:7710–7717

    CAS  Google Scholar 

  13. Steinert PM, Kim SY, Chung SI, Marekov LN (1996) J Biol Chem 271:26242–26250

    Article  CAS  Google Scholar 

  14. Nemes Z, Marekov LN, Fesüs L, Steinert PM (1996) Proc Natl Acad Sci 96:8402–8407

    Article  Google Scholar 

  15. Phillips MA, Stewart BE, Qin Q, Chakravarty R, Floyd EE, Jetten AM, Rice RH (1990) Proc Natl Acad Sci 87:9333–9337

    Article  CAS  Google Scholar 

  16. Phillips MA, Qin Q, Mehrpouyan M, Rice RH (19923) Biochemistry 32:11057–11063

    Article  CAS  Google Scholar 

  17. Pilgram GSK, Vissers DCJ, van der Meulen H, Pavel S, Lavrijsen SPM, Bouwstra JA, Koerten HK (2001) J Invest Dermatol 117:710–717

    Article  CAS  Google Scholar 

  18. Hennies HC, Kuster W, Wiebe V, Krebsova A, Reis A (1998) Am J Hum Genet 62:1052–1061

    Article  CAS  Google Scholar 

  19. Gish W (1996–2002) http://blast.wustl.edu/blast/

  20. Godzik A, Kolinski A, Skolnick J (1992) J Mol Biol 227:227–238

    Article  CAS  Google Scholar 

  21. McGuffin LJ, Bryson K, Jones DT (2000) Bioinformatics 16:404–405

    Article  CAS  Google Scholar 

  22. Lüthy R, Bowie JU, Eisenberg D (1992) Nature 356:83–85

    Article  Google Scholar 

  23. Sabnis Y, Desai PV, Rosenthal PJ, Avery MA (2003) Prot Sci 12:501–509

    Article  CAS  Google Scholar 

  24. Jones TA, Thirup S (1986) EMBO J 5:819–822

    CAS  Google Scholar 

  25. Stouten PFW, Froemmel C, Nakamura H, Sander C (1993) Mol Simul 10:97–120

    CAS  Google Scholar 

  26. Greengard L, Rokhlin VI (1987) J Comp Phys 73:325–348

    Article  Google Scholar 

  27. Verlet L (1967) Phys Rev 159:98–103

    Article  CAS  Google Scholar 

  28. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1992) J Appl Cryst 26:283–291

    Article  Google Scholar 

  29. Merritt EA, Bacon DJ (1997) Method Enzymol 277:505–525

    Article  CAS  Google Scholar 

  30. Kraulis PJ (1991) J Appl Cryst 24:946–950

    Article  Google Scholar 

  31. SYBYL 6.7 (1995) Tripos Assoc. Inc., St. Louis, MO

  32. Ahvazi B, Kim HC, Kee SH, Nemes Z, Steinert PM (2002) EMBO J 21:2055–2067

    Article  CAS  Google Scholar 

  33. Ahvazi B, Boeshans KM, Jang S-I, Kalinin P, Steinert PM (2002) Minerva Biotecnol 14:165–169

    Google Scholar 

  34. Ahvazi B, Boeshans KM, Idler W, Baxa U, Steinert PM (2003) J Biol Chem 278:23834–23841

    Article  CAS  Google Scholar 

  35. Ahvazi B, Boeshans KM, Steinert PM (2004) J Biol Chem 279:26716–26725

    Article  CAS  Google Scholar 

  36. Menon GK, Elias PM (1991) Arch Dermatol 127:57–63

    Article  CAS  Google Scholar 

  37. Hennings H, Michael D, Cheng C, Steinert P, Holbrook K, Yuspa SH (1980) Cell 19:245–254

    Article  CAS  Google Scholar 

  38. Ahvazi B, Steinert PM (2003) Exp Mol Med 35:228–242

    CAS  Google Scholar 

  39. Ahvazi B, Boeshans KM, Rastinejad F (2004) J Struct Biol 147:200–207

    Article  CAS  Google Scholar 

  40. Weiss MS, Jabs A, Hilgenfeld R (1998) Nat Struct Biol 5:676

    Article  CAS  Google Scholar 

  41. Jabs A, Weiss MS, Hilgenfeld R (1999) J Mol Biol 286:291–304

    Article  CAS  Google Scholar 

  42. Stoddard BL, Pietrokovski S (1998) Nat Struct Biol 5:3–5

    Article  CAS  Google Scholar 

  43. Folkers G (1998) In: Codding PW (ed) Structure-based drug design: experimental and computational approaches. Kluwer Academic Publisher, Norwell, MA, pp 271–283

    Google Scholar 

  44. Candi E, Tarcsa E, Idler WW, Kartasova T, Marekov LN, Steinert PM (1999) J Biol Chem 274:7226–7237

    Article  CAS  Google Scholar 

  45. Ludwig M, Pattridge K, Metzger A, Dixon M, Eren M, Feng Y, Swenson R (1997) Biochemistry 36:1259–1280

    Article  CAS  Google Scholar 

  46. Heroux A, White E, Ross L, Davis R, Borhani D (1999) Biochemistry 38:14495–14506

    Article  CAS  Google Scholar 

  47. Stewart D, Sarkar A, Wampler J (1990) J Mol Biol 214:253–260

    Article  CAS  Google Scholar 

  48. Lin LN, Brandts JF (1993) Biochemistry 22:564–573

    Article  Google Scholar 

  49. Scherer G, Kramer M, Schutkowski M, Reimer U, Fischer G (1998) J Am Chem Soc 120:5568–5579

    Article  CAS  Google Scholar 

  50. Schiene-Fischer C, Fischer G (2001) J Am Chem Soc 123:6227–6231

    Article  CAS  Google Scholar 

  51. Reimer U, Fischer G (2002) Biophys Chemist 96:203–212

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Henry Hennings of NCI’s Laboratory of Cellular Carcinogenesis and Tumor Formation for critical review of our manuscript. We are indebted to Dr. Ellis Kempner for stimulating discussion and critical review of this manuscript. This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.

Author information

Authors and Affiliations

  1. X-ray Crystallography Facility/Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892-8024, USA

    Karen M. Boeshans & Bijan Ahvazi

  2. Department of Chemistry, University of Toledo, Toledo, OH, 43606, USA

    Timothy C. Mueser

  3. X-ray Crystallography Facility, NIAMS, MSC 8024, 50 South Dr., Building 50, Room 1345, Bethesda, MD, 20892-8024, USA

    Bijan Ahvazi

Authors
  1. Karen M. Boeshans
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Timothy C. Mueser
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bijan Ahvazi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bijan Ahvazi.

Additional information

This paper is dedicated to the memory of Dr. Peter M. Steinert (April 7, 2003).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boeshans, K.M., Mueser, T.C. & Ahvazi, B. A three-dimensional model of the human transglutaminase 1: insights into the understanding of lamellar ichthyosis. J Mol Model 13, 233–246 (2007). https://doi.org/10.1007/s00894-006-0144-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-006-0144-9

Keywords

Search

Navigation