Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase I activity from the formation of cross-links and esters to the hydrolysis of glutamine

Zoltán Nemes, Máté Demény, Lyuben N. Marekov, L. Fésüs, Peter M. Steinert

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

The loss of transglutaminase I enzyme (TGase 1) activity causes lamellar ichthyosis. Recessive X-linked ichthyosis (XI) results from accumulation of excess cholesterol 3-sulfate (CSO4) in the epidermis but the pathomechanism how elevated epidermal CSO4 causes ichthyosis is largely unknown. Here we provide evidence that XI is also a consequence of TGase 1 dysfunction. TGase 1 is a key component of barrier formation in keratinocytes: it participates in the cross-linking of cell envelope (CE) structural proteins, and also forms the lipid bound envelope by esterification of long chain ω- hydroxyceramides onto CE proteins. Using involucrin and an epidermal ω- hydroxyceramide analog as substrates, kinetic analyses revealed that at membrane concentrations above 4 mol%, CSO4 caused a marked and dose- dependent inhibitory effect on isopeptide and ester bond formation. Sequencing of tryptic peptides from TGase 1-reacted involucrin showed a large increase in deamidation of substrate glutamines. We hypothesize that supraphysiological levels of CSO4 in keratinocyte membranes distort the structure of TGase 1 and facilitate the access of water into its active site causing hydrolysis of substrate glutamine residues. Our findings provide further evidence for the pivotal role of the TGase 1 enzyme in CE formation.

Original languageEnglish
Pages (from-to)2636-2646
Number of pages11
JournalJournal of Biological Chemistry
Volume275
Issue number4
DOIs
Publication statusPublished - Jan 28 2000

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Transglutaminases
X-Linked Ichthyosis
Glutamine
Sulfates
Hydrolysis
Esters
Cholesterol
Keratinocytes
Substrates
Lamellar Ichthyosis
Membranes
Ichthyosis
Esterification
Enzymes
Epidermis
Catalytic Domain
Proteins
Lipids
Peptides
Kinetics

ASJC Scopus subject areas

  • Biochemistry

Cite this

Cholesterol 3-sulfate interferes with cornified envelope assembly by diverting transglutaminase I activity from the formation of cross-links and esters to the hydrolysis of glutamine. / Nemes, Zoltán; Demény, Máté; Marekov, Lyuben N.; Fésüs, L.; Steinert, Peter M.

In: Journal of Biological Chemistry, Vol. 275, No. 4, 28.01.2000, p. 2636-2646.

Research output: Contribution to journalArticle

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