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2013 ; 1830
(6
): 3489-96
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Disulfide reduction abolishes tissue factor cofactor function
#MMPMID23434438
Krudysz-Amblo J
; Jennings ME 2nd
; Knight T
; Matthews DE
; Mann KG
; Butenas S
Biochim Biophys Acta
2013[Jun]; 1830
(6
): 3489-96
PMID23434438
show ga
BACKGROUND: Tissue factor (TF), an in vivo initiator of blood coagulation, is a
transmembrane protein and has two disulfides in the extracellular domain. The
integrity of one cysteine pair, Cys186-Cys209, has been hypothesized to be
essential for an allosteric "decryption" phenomenon, presumably regulating TF
procoagulant function, which has been the subject of a lengthy debate. The
conclusions of published studies on this subject are based on indirect evidences
obtained by the use of reagents with potentially oxidizing/reducing properties.
METHODS: The status of disulfides in recombinant TF1-263 and natural placental TF
in their non-reduced native and reduced forms was determined by
mass-spectrometry. Functional assays were performed to assess TF cofactor
function. RESULTS: In native proteins, all four cysteines of the extracellular
domain of TF are oxidized. Reduced TF retains factor VIIa binding capacity but
completely loses the cofactor function. CONCLUSION: The reduction of TF
disulfides (with or without alkylation) eliminates TF regulation of factor VIIa
catalytic function in both membrane dependent FX activation and membrane
independent synthetic substrate hydrolysis. GENERAL SIGNIFICANCE: Results of this
study advance our knowledge on TF structure/function relationships.
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