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BIOCHEMISTRY
 
 

Dr. Qing-xin Hua

Associate Professor

Pub Med:

Dr. Qing-xin Hua

Dr. Hua's research focuses on the solution structure, folding, binding and dynamics of proteins by use of NMR and other biophysico-chemical methods.

Insulin, insulin mutants and insulin family,

Since 1989 a series of NMR studies of insulin and its mutants were carried out, from which the solution structure, the folding characteristics, binding and stability of insulin had been extensively explored. Nine structural coordinates of insulin and its mutants have been deposited in the Brookhaven Data Bank (PDB entries: 1HIQ, 1HIS, 1HIT, 1SJT, 1SJU, 1VKS, 1VKT, 1XGL and 2HIU).

Transcriptional factor

MODY (Maturity-Onset Diabetes Mellitus of the Young): The monogenic form of human non-insulin-dependent diabetes mellitus arises from mutations in genes expressed in the pancreatic beta cell. The diabetes-associated mutations of its N-terminal leucine-rich helical dimerization motif destabilize. Impaired dimerization provides a molecular mechanism of metabolic transcriptional deregulation in diabetes mellitus. (PDB code: 1DT8).

CREB (cAMP-Response-Element Binding Protein) A model of transcriptional activator-coactivator recognition is provided by the mammalian CREB kinase-inducible activation domain (pKID) and the KIX domain of coactivator CBP. NMR study found that such nascent structure of pKID is independent of serine phosphorylation and correlates with the relative extent of engagement of the two a-helices in the pKID-KIX complex.

Mini-Chaperone (the apical domain of thermophilic GroEL)


Temperature (rather than chemical denaturants) was used to unfold mesophilic protein substrates in the presence of a native mini-chaperone. 15N-HSQC spectra were obtained at 50º C in the absence and presence of the target proteins: partially unfolded monomer-DKP-insulin and a partially folded SRY HMG box. The result supports the hypothesis that the apical domain contains a single and universal surface for binding of molten proteins.

Selected References

  • Nakagawa, S. H., Zhao, M. Hua, Q. X., Hu, S. Q., Jia, W., Weiss, M. A. "Chiral mutagenesis of insulin. Foldability and function are invesely regulated by a stereospecific switch in the B chain. " Biochemistry. (2005) 44:4984-4999.

  • Hua, Q. X., and Weiss, M. A. "Mechanism of Insulin Fibrillation: The Structure of Insulin Under Amyloidogenic Conditions Resembles A Protein-Folding Intermediate." Biol. Chem. (2004) 279: 21449-21460.

  • Hua, Q. X., Nakagawa, S. H., Wilken, J., Ramos, R. R., Jia, W., Bass, J., and Weiss, M. A. "A divergent INS protein in Caenorhabditis elegans structurally resembles human insulin and activates the human insulin receptor." Genes Dev. (2003) 17:826-831.

  • Q. X. Hua., W. H. Jia., B. P. Bullock., J. F. Habener., and M. A. Weiss. "Diabetes-associated mutations in insulin: consecutive residues in the B chain contact distinct domains of the insulin receptor." Biochemistry (1998) 37:5858-5866.

  • Q. X. Hua, I. Dementieva, M. Walsh, K. Hallenga, M. A. Weiss and A. Joachimiak. "A Thermophilic Apical Domain Contains a Conserved Protein-Binding Surface: a Combined Crystallographic and NMR Study with Implications for GroEL-Substrate Interactions." J. Mol. Biol. (2001) 306:513-525.

  • Q. X. Hua., M. Zhao., N. Narayana., S. H. Nakagawa., W. Jia., and M. A. Weiss. "Diabetes-associated Mutations in a b-Cell Transcription Factor Destabilize an Anti-Parallel "Mini-Zipper." Proc. Natl. Acad. Sci. USA (2000) 97:1999-2004.

  • Q. X. Hua., W. H. Jia., B. P. Bullock., J. F. Habener., and M. A. Weiss. "Transcriptional Activator-Coactivator Recognition: Nascent Folding of a Kinase-Inducible Transactivation Domain Predicts Its Structure on Coactivator Binding". Biochemistry (1998) 37:5858-5866.

  • Q. X. Hua., S. Q. Hu., W. H. Jia., Y. C. Chu., G. T. Burke., S. H. Wang., R.Y.Wang., P. G. Katsoyannis, and M. A. Weiss. "Mini-proinsulin and Mini-IGF-I: Homologous Protein Sequences Encoding Non-homologous Structures" J. Mol. Biol. (1998) 277:103-118.

  • Q. X. Hua., S. Q. Hu., H. Frank., W. H. Jia., Y. C. Chu., S. H. Wang., G. T. Burke., P. G. Katsoyannis, and M. A. Weiss. "Mapping the Functional Surface of insulin by Design: Structure and Function of a Novel A-Chain Analogue" J. Mol. Biol. (1996) 264:390-403.

  • Q. X. Hua., L. Nahri., W. Jia., T. Arakawa., R. Rosenfeld., N. Hawkins., J. Miller., and M. A. Weiss. "Native and Non-native Structure in a Protein-folding Intermediate: Spectroscopic Studies of Partially Reduced IGF-I and an Engineered Alanine Model" J. Mol. Biol. (1996) 259, 297-313.

  • Q. X. Hua., S. Gozani., R. Chance., J. A. Hoffmann., B. H. Frank, and M. A. Weiss. "Structure of a Protein in a Kinetic Trap" Nature: Struct. Biol. (1995) 2,129-138.

  • Q. X. Hua., S. E. Shoelson., M. Kochoyan., and M. A. Weiss. "Receptor Binding Redefined by a Structural Switch in the Solution Structure of a Mutant Human Insulin." Nature. (1991) 354:238-241.