Tyrosine-O-sulfation is a common post-translational modification (PTM) of proteins following the cellular secretory pathway. First described in human fibrinogen, tyrosine-O-sulfation has long been associated with the modulation of protein–protein interactions in several physiological processes. A number of relevant interactions for hemostasis are largely dictated by this PTM, many of which involving the serine proteinase thrombin (FIIa), a central player in the blood-clotting cascade. Tyrosine sulfation is not limited to endogenous FIIa ligands and has also been found in hirudin, a well-known and potent thrombin inhibitor from the medicinal leech, Hirudo medicinalis. The discovery of hirudin led to successful clinical application of analogs of leech-inspired molecules, but also unveiled several other natural thrombin-directed anticoagulant molecules, many of which undergo tyrosine-O-sulfation. The presence of this PTM has been shown to enhance the anticoagulant properties of these peptides from a range of blood-feeding organisms, including ticks, mosquitos and flies. Interestingly, some of these molecules display mechanisms of action that mimic those of thrombin's bona fide substrates.
Tyrosine-O-sulfation is a widespread affinity enhancer among thrombin interactors
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Jorge Ripoll-Rozada, Joshua W. C. Maxwell, Richard J. Payne, Pedro José Barbosa Pereira; Tyrosine-O-sulfation is a widespread affinity enhancer among thrombin interactors. Biochem Soc Trans 28 February 2022; 50 (1): 387–401. doi: https://doi.org/10.1042/BST20210600
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