bims-supasi Biomed News
on Sulfation pathways and signalling
Issue of 2022‒01‒09
three papers selected by
Jonathan Wolf Mueller
University of Birmingham

  1. Biochem Soc Trans. 2022 Jan 07. pii: BST20210600. [Epub ahead of print]
      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.
    Keywords:  anticoagulant; blood clotting; post translational modification; thrombin inhibitor; tyrosine sulfation
  2. Front Mol Biosci. 2021 ;8 771447
      Mass spectrometry-based high-sensitivity mapping of terminal glycotopes relies on diagnostic MS2 and/or MS3 ions that can differentiate linkage and define the location of substituents including sulfates. Unambiguous identification of adult zebrafish glycotopes is particularly challenging due to the presence of extra β4-galactosylation on the basic building block of Galβ1-4GlcNAc that can be fucosylated and variably sialylated by N-acetyl, N-glycolyl, or deaminated neuraminic acids. Building on previous groundwork that have identified various organ-specific N- and O-glycans of adult zebrafish, we show here that all the major glycotopes of interest can be readily mapped by direct nano-LC-MS/MS analysis of permethylated glycans. Homing in on the brain-, intestine-, and ovary-derived samples, organ-specific glycomic reference maps based on overlaid extracted ion chromatograms of resolved glycan species, and composite charts of summed intensities of diagnostic MS2 ions representing the distribution and relative abundance of each of the glycotopes and sialic acid variants were established. Moreover, switching to negative mode analysis of sample fractions enriched in negatively charged glycans, we show, for the first time, that a full range of sulfated glycotopes is expressed in adult zebrafish. In particular, 3-O-sulfation of terminal Gal was commonly found, whereas terminal sulfated HexNAc as in GalNAcβ1-4GlcNAc (LacdiNAc), and 3-O-sulfated hexuronic acid as in HNK-1 epitope (SO3-3GlcAβ1-3Galβ1-4GlcNAc) were identified only in the brain and not in the intestine or ovaries analyzed in parallel. Other characteristic structural features of sulfated O- and N-glycans along with their diagnostic ions detected in this discovery mode sulfoglycomic work collectively expand our adult zebrafish glycome atlas, which can now allow for a more complete navigation and probing of the underlying sulfotransferases and glycosyltransferases, in search of the functional relevance of zebrafish-specific glycotopes. Of particular importance is the knowledge of glycomic features distinct from those of humans when using adult zebrafish as an alternative vertebrate model, rather than mouse, for brain-related glyco-neurobiology studies.
    Keywords:  HNK-1 epitope; glycomics; glycotopes; mass spectrometry; sulfoglycomics; zebrafish
  3. Am J Med Genet A. 2022 Jan 06.
      Biallelic IMPAD1 pathogenic variants leads to deficiency of GPAPP (Golgi 3-prime phosphoadenosine 5-prime phosphate 3-prime phosphatase) protein and clinically causes chondrodysplasia, which is characterized by short stature with short limbs, craniofacial malformations, cleft palate, hand and foot anomalies, and various radiographic skeletal manifestations. Here we describe prenatal presentation of GPAPP deficiency caused by novel biallelic pathogenic variants, 2 base pair duplication in exon 2 of IMAPD1 gene in a patient of Asian-Indian origin. Further we report on diagnostic clues of prenatal presentation of GPAPP deficiency through ultrasonography, fetal MRI, and postmortem findings. We also provide evidence of pathophysiology of underlying GPAPP deficiency in the form of disorganization and dysplastic chondrocytes and reduced sulfation of glycoproteins through histopathology of cartilage similar to that described in mice IMPAD1 homozygous mutant model.
    Keywords:  GPAPP deficiency; cleft palate; elbow joint dysplasia; hitch-hiker thumb; lateral deviation of fifth toe