Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Li, T; Sánchez-Murcia, PA; Nidetzky, B.
Structural instability impairs function of the UDP-xylose synthase 1 Ile181Asn variant associated with short-stature genetic syndrome in humans
FEBS LETT. 2026; PMID 155157
Doi: 10.1002/1873-3468.70277
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Sánchez Murcia Pedro Alejandro
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- Abstract:
- Glycosaminoglycan assembly on proteoglycans involves a common tetrasaccharide linker that starts with xylose attached to a serine on the protein. Defective linker biosynthesis caused by a missense mutation of human UDP-xylose synthase (hUXS1) is associated with connective tissue disorders characterized by skeletal abnormality and short stature. The Ile181Asn variant of hUXS1 was reported as inactive in releasing UDP-xylose from UDP-glucuronic acid. Here, we show that Ile181Asn-hUXS1 exhibited catalytic properties similar to the wild-type enzyme but featured a significant decrease in stability, expressed in melting temperature lowered from 48.2 degrees C to 35.2 degrees C. At 37 degrees C, Ile181Asn-hUXS1 was similar to 10-fold less stable and more prone to precipitation than wild-type hUXS1. The loss of function in Ile181Asn-hUXS1 is thus explained by instability, consistent with molecular dynamics simulations predicting structural destabilization.
- Find related publications in this database (Keywords)
- linkeropathy
- protein dimer
- proteoglycan
- stability
- tetrasaccharide linker
- UDP-xylose
- UDP-xylose synthase UXS1