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

DOI: 10.1007/s00894-006-0144-9

Cite this article as:
Boeshans, K.M., Mueser, T.C. & Ahvazi, B. J Mol Model (2007) 13: 233. doi:10.1007/s00894-006-0144-9

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.

Figure

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.

Keywords

Keratinocyte transglutaminase 1Lamellar ichthyosisMutationsMetal ionsIsomerizationMolecular modeling

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

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