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

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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.

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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

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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.

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Correspondence to Bijan Ahvazi.

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

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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

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

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