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Articles by K. H Khoo
Total Records ( 13 ) for K. H Khoo
  N Suzuki , T. H Su , S. W Wu , K Yamamoto , K. H Khoo and Y. C Lee
 

We previously showed that the expression of (Gal1-4Gal)-bearing glycoproteins among birds is related to their phylogeny. However, precise structures of (Gal1-4Gal)-containing N-glycans were only known for pigeon egg white glycoproteins and IgG. To compare structural features of (Gal1-4Gal)-containing N-glycans from other species, we analyzed N-glycans of gull egg white (GEW)-glycoproteins, ovomucoid, and ovotransferrin, and gull egg yolk IgG by HPLC, mass spectrometry (MS), and MS/MS analyses. GEW-glycoproteins included neutral, monosialyl, and disialyl N-glycans, and some of them contained Gal1-4Gal sequences. Bi-, tri-, and tetra-antennary oligosaccharides that lacked bisecting GlcNAc were the major core structures, and incomplete -galactosylation and sialylation as well as the presence of diLacNAc on the branches generated microheterogeneity of the N-glycan structures. Moreover, unlike pigeon egg white glycoproteins, the major sialylation in GEW-glycoproteins is 2,3-, but not 2,6-linked sialic acids (NeuAc). In addition to the complex-type oligosaccharide, hybrid-type oligosaccharides that lack bisecting GlcNAc were also abundant in GEW-glycoproteins. Gull egg yolk IgG also contained Gal1-4Galβ1-4GlcNAcβ1- sequences, but unlike pigeon IgG, no Gal1-4Galβ1-4Galβ1-4GlcNAcβ1- sequence was detected. Bi- and tri-antennary complex-type oligosaccharides with bisecting GlcNAc and with core fucosylation as well as high-mannose-type oligosaccharides were the major structures in gull IgG. Our data indicated that some N-glycans from both GEW-glycoproteins and gull IgG contain the Gal1-4Galβ1-4GlcNAcβ1- sequence, but the ratio of -Gal-capped residues to non--Gal-capped residues in the nonreducing termini of N-glycans is much lower than that in those of pigeon glycoproteins.

  K. H Khoo , A. C Joerger , S. M.V Freund and A. R. Fersht
 

The core domain of the tumour suppressor p53 is of inherently low thermodynamic stability and also low kinetic stability, which leads to rapid irreversible denaturation. Some oncogenic mutations of p53 act by just making the core domain thermosensitive, and so it is the target of novel anti-cancer drugs that bind to and stabilise the protein. Increasing the stability of the unstable core domain has also been crucial for biophysical and structural studies, in which a stabilised quadruple mutant (QM) is currently used. We generated an even more stabilised hexamutant (HM) by making two additional substitutions, Y236F and T253I, to the QM. The residues are found in the more stable paralogs p63 and p73 and stabilise the wild-type p53 core domain. We solved the structure of the HM core domain by X-ray crystallography at 1.75 Å resolution. It has minimal structural changes from QM that affect the packing of hydrophobic core residues of the β-sandwich. The full-length HM was also fully functional in DNA binding. HM was more stable than QM at 37°C. Anomalies in biophysics and spectroscopy in urea-mediated denaturation curves of HM implied the accumulation of a folding intermediate, which may be related to those detected in kinetic experiments. The two additional mutations over-stabilise an unfolding intermediate. These results should be taken into consideration in drug design strategies for increasing the stability of temperature-sensitive mutants of p53.

 
 
 
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