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BIOCHEMISTRY
 
 
Weiss

Dr. Michael Weiss

Professor

Pub Med:

Dr. Michael Weiss

Research in the Weiss laboratory focuses on two areas: control of gene expression, and protein folding and misfolding. Links are made to clinical phenotypes or disease mechanisms. Studies of gene expression include analysis of mammalian and viral transcription factors.

1. Protein-nucleic acid interactions; structural aspects of gene regulation. Application to the birth defects, regulation of metabolism and nuclear oncoproteins.
2. Peptide hormones; principles of receptor recognition; insulin and diabetes mellitus; structure-activity relationships and protein design. Post-receptor protein-phosphoprotein interactions and relation to malignant transformation. Application to cytoplasmic oncoproteins.
3. Prokaryotic Transcriptional Regulation and Lambdoid Phages with application to pathogenesis and infectious disease.

Mutations or deletions in human transcription factors can, for example, deregulate organogenesis and cause genetic susceptibility to malignancy. A model is provided by transcriptional factors regulating testicular differentiation. Gonadal dysgenesis and gonadoblastoma are associated with mutations or deletions in the Y chromosome (interval 1A1) or chromosome 9 (interval 9p24), mapped to genes SRY or DMTR1/DMTR2, respectively. Biochemical and structural studies of the DNA-binding motifs encoded by the loci are in progress.

Studies of protein folding and misfolding focus on insulin and diabetes-related transcription factors in the pancreatic beta cell. Mutations in the latter are associated with impaired glucose-stimulated insulin secretion leading to maturity-onset diabetes of the young. Structural studies focus on a novel four-helix bundle in hepatic nuclear factor 1a.

Selected References

  • Huang, K., Maiti, N. C., Phillips, N. B., Carey, P. R., and Weiss, M. A. (2006) “Structure-Specific Effects of Protein Topology on Cross-ß Assembly: Studies of Insulin Fibrillation.” Biochemistry 45: 10278-10293.

  • Hua, Q. X., Mayer, J. P., Jia, W., Zhang, J., and Weiss, M. A. (2006) “The Folding Nucleus of the Insulin Superfamily.  A flexible peptide model foreshadows the native state.” J. Biol. Chem. 281: 28131-28142.

  • Narayana, N., Phillips, N. B., Hua, Q. X., Jia, W., and Weiss, M. A. (2006) “Diabetes Mellitus due to Misfolding of a ß-cell Transcription Factor. Stereospecific Frustration of a Schellman Motif in HNF-1alpha.” J. Mol Biol. 362: 414-419.

  • Hua, Q., Nakagawa, S. H., Hu, S, Jia, W, and Weiss, M. A. (2006) “Toward the Active Conformation of Insulin. Stereospecific Modulation of a Structural Switch in the B Chain.” J. Biol. Chem. 281: 24900-24909.

  • Li, B., Phillips, N. B., Jancso-Radek, A., Ittah, V., Singh, R., Jones, D. N., Haas, E., and Weiss, M. A. (2006) “SRY-directed DNA bending and human sex reversal: reassessment of a clinical mutation uncovers a global coupling between the HMG box and its tail.” J. Mol. Biol. 360: 310-328.

  • Nakagawa, S. H., Hua, Q. X., Hu, S. Q., Jia, W., Katsoyannis, P. G., and Weiss, M. A. (2006) “Chiral mutagenesis of insulin. Contribution of the B20-B23 ß-turn to activity and stability.” J. Biol. Chem. 281: 22386-22396.

  • Hua, Q. X., Liu, M., Hu, S. Q., Jia, W., Arvan, P., and Weiss, M. A. (2006) “A Conserved Histidine in Insulin is required for the Foldability of Human Proinsulin: Structure and function Of an AlaB5 analog.” J Biol Chem. (in press).

  • Phillips, N. B., Jancso-Radek, A., Ittah, V., Singh, R., Chan, G., Haas, E., and Weiss, M.A. (2006) “SRY and Human Sex Determination: the Basic Tail of the HMG Box Functions as a Kinetic Clamp to Augment DNA Bending.” J. Mol. Biol. (2006) 358: 172-192.

  • Zhang, W., Li, B., Singh, R., Narendra, U., Zhu, L., and Weiss, M.A. (2006) “Regulation of sexual dimorphism: mutational and chemogenetic analysis of the doublesex DM domain.” Mol. Cell. Biol. 26: 535-547.

  • Huang K., Dong J, Phillips NB, Carey PR, Weiss MA. (2005) “Proinsulin Is Refractory to Protein Fibrillation: TOPOLOGICAL PROTECTION OF A PRECURSOR PROTEIN FROM CROSS-{beta} ASSEMBLY.” J Biol Chem. 280:42345-42355.

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

  • Xu B, Hu SQ, Chu YC, Huang K, Nakagawa SH, Whittaker J, Katsoyannis PG, Weiss MA.(2004) "Diabetes-associated mutations in insulin: consecutive residues in the B chain contact distinct domains of the insulin receptor." Biochemistry. 43356-43372.

  • Huang K, Xu B, Hu SQ, Chu YC, Hua QX, Qu Y, Li B, Wang S, Wang RY, Nakagawa SH, Theede AM, Whittaker J, De Meyts P, Katsoyannis PG, Weiss MA. (2004)"How insulin binds: the B-chain alpha-helix contacts the L1 beta-helix of the insulin receptor." J. Mol. Biol. 341:529-550..

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

  • Qiao, Z. S., Min, C. Y., Hua, Q. X., Weiss, M. A., and Feng, Y. M. (2003) In vitro refolding of human proinsulin: Kinetic intermediates, putative disulfide-forming pathway, folding initiation site and potential role of C-peptide in folding process. J. Biol. Chem. 278:17800-17809.

  • Dong, J., Wan, Z., Popov, M., Carey, P. R., and Weiss, M. A. (2003) Insulin assembly damps conformational fluctuations: Raman analysis of amide I line widths in native states and fibrils. J. Mol. Biol. 330:431-442.

  • Hua, Qing-Xin; Jia, Wenhua; Frank, Bruce H.; Phillips, Nelson F. B.; Weiss, Michael A. (2002) A Protein Caught in a Kinetic Trap: Structures and Stabilities of Insulin Disulfide Isomers. Biochemistry 41, 14700-14715

  • Hua, Q. X., Chu, Y.-C., Jia, W., Phillips, N. F., Wang, R.-Y., Katsoyannis, P. G., and Weiss, M. A. (2002) Mechanism of insulin chain combination. Asymmetric roles of A-chain a-helices in disulfide pairing. J Biol Chem. 2002 Nov 8;277(45):43443-53

  • Narendra, U., Zhu, L., Li, B., Wilken, J., and Weiss, M. A. (2002) Sex-specific gene regulation: the Doublesex DM motif is a bipartite DNA-binding domain. J Biol Chem. 2002 Nov 8;277(45):43463-73

  • Weiss, M. A., Hua, Q. X., Jia, W., Nakagawa, S. H., Chu, Y.-C., and Katsoyannis, P. G. (2002) Activities of insulin analogues at position 8 are uncorrelated with thermodynamic stability in Insulin & Related Proteins-Structure to Function and Pharmacology (Dieken, M. L., Federwisch, M., and De Meyts, P., eds.). Dordrecht, The Netherlands: Kluwer Academic Publishers, 103-119

  • Lachenman, M., Ladbury, J. E., Phillips, N. B., Narayana, N., Qian, X., Weiss, M. A. (2002) The hidden thermodynamics of a zinc finger. J. Mol. Biol. 316: 969-984.
        Appendix: Lachenmann, M., Stern, A. S., and Weiss, M. A. (2002)
        Visualization of 1H-NMR ring currents in a zinc finger.
         J. Mol. Biol.316: 984-989.

  • Xu, B., Hua, Q. X., Nakagawa, S. H., Jia, W., Chu, Y.-C., Katsoyannis, P. G., and Weiss, M. A. (2002) Chiral Mutagenesis of Insulin's Hidden Receptor-Binding Surface: Structure of an Allo-isoleucineA2 Analogue. J. Mol. Biol. 316: 435-441.

  • Weiss, M. A., Nakagawa, S. H., Jia, W., Xu, B., Hua, Q. X., Chu, Y.-C., Wang, R. Y., and Katsoyannis, P. G. Protein Structure and the Spandresl of San Marco: Insulin’s Receptor-Binding Surface Is Buttressed by an Invariant Leucine Essential for Its Stability
    Biochemistry, (2002) 41(3): 809-819.

  • Bin Xu, Qing-xin Hua, Satoe H. Nakagawa, Wenhua Jia, Ying-Chi Chu, Panayotis G. Katsoyannis, and Michael A. Weiss. A Cavity-Forming Mutation in Insulin Induces Segmental Unfolding of a Surrounding a-Helix. Protein Sci. 2002 Jan;11(1):104-116.

  • Weiss, M. A., Wan, Z., Zhao, M., Chu, Y.-C., Nakagawa, S. H., Burke, G. T., Jia, W., Helmich, R., Katsoyannis, P. G. Non-standard insulin design: structure-activity relationships at the periphery of the insulin receptor. J. Mol. Biol. (2002) 315(2): 103-111

  • Biaoru Li, Wei Zhang, Ging Chan, Agnes Jancso-Radek, Shuhe Liu, and Michael A. Weiss. Human Sex Reversal Due to Impaired Nuclear Localization of SRY: a Clinical Correlation. J. Biol. Chem. (2001) 276: 46480-46484

  • Qing-Xin Hua, Satoe H. Nakagawa, Wenhua Jia, Shi-Quan Hu, Ying-Chi Chu, Panayotis G. Katsoyannis, and Michael A. Weiss. Hierarchical Protein Folding: Asymmetric Unfolding of an Insulin Analogue Lacking the A7-B7 Inter-Chain Disulfide Bridge. Biochemistry (2001), 40, 12299-12311

  • Michael A. Weiss, Qing-Xin Hua, Wenhua Jia, Satoe H. Nakagawa, Ying-Chi Chu, Shi-Quan Hu, and Panayotis G. Katsoyannis. Activities of Monomeric Insulin Analogs at Position A8 are Uncorrelated with their Thermodynamic Stabilities. J. Biol. Chem. (2001) 276: 40018-40024

  • Dong J, Wan ZL, Chu YC, Nakagawa SN, Katsoyannis PG, Weiss MA, Carey PR. Isotope-Edited Raman Spectroscopy of Proteins: a General Strategy to Probe Individual Peptide Bonds with Application to Insulin. J Am Chem Soc. (2001) Aug 15;123(32):7919-7920, PMID: 11493071

  • Narendra Narayana, Qing-xin Hua, and Michael A. Weiss. The dimerization domain of HNF-1a: structure and plasticity of an intertwined four-helix bundle with application to diabetes mellitus. J. Mol. Biol. (2001) July; 310(3):635-658

  • Weiss, M. A., "Floppy SOX: Mutual Induced Fit in HMG (High-Mobility Group) Box-DNA Recognition" Molecular Endocrinology (2001) 15(3): 353-362

  • Ukiyama, E., Jancso-Radek, A., Li, B., Milos, L., Zhang, W., Phillips, N.B., Norikawa, N., King, C., Chan, G., Haqq, C. M., Radek, J.T., Poulat, F., Donahoe, P.K. and Weiss, M.A., "SRY amd Architectural Gene Regulation: The kinetic Stability of a Bent Protein-DNA COmplex Can Regulate Its Transcriptional Potency" Molecular Endocrinology (2001) 15:363-377

  • Hua, Q. X., Dementieva, I. S., Walsh, M. A., Hallenga, K., Weiss, M. A., and Joachimiak, A. A Thermophilic Mini-chaperonin Contains a Conserved Polypeptide-binding Surface: Combined Crystallographic and NMR Studies of the GroEL Apical Domain with Implications for Substrate Interactions. J. Mol. Biol. (2001) 306:513-525.

  • Wang, B., Stern.S., and Weiss, M. A., "Aromatic Ring Currents at a Protein Surface: Use of 1H-NMR Chemical Shifts to Refine The Structure of a Naked Beta Sheet" Journal of Biomolecular Structure & Dynamics (2000):95-108

  • Zhu, L., Wilken, J., Phillips, N.B., Narendra, U., Chan, G., Stratton S.M., Kent, S.B., and Weiss, M. A., "Sexual dimorphism in diverse metazoans is regulated by a novel class of intertwined zinc fingers" Genes & Development (2000) 14:1750-1764

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

  • Weiss, M. A., Hua, Q. X., Jia, W., Chu, Y. C., Wang, R.Y., and Katsoyannis, P.G. "Hierarchical Protein "Un Design": Insulin's Intrachain Disulfide Bridge Tethers a Recognition Alpha-Helix" Biochemistry (2000), 39:15429-15440

  • Benevides, J. M., Chan, G., Lu, X. J., Olson, W. K., Weiss, M. A., and Thomas Jr., G. J., "Protein-Directed DNA Structure. I. Raman Spectroscopy of a High-Mobility-Group Box with Application to Human Sex Reversal." Biochemistry (2000) 39:537-547.

  • Benevides, J. M., Li, T., Lu, X. J., Srinivasan, A.R., Olson, W. K., Weiss, M. A., and Thomas Jr., G. J., "Protein-Directed DNA Structure II. Raman Spectroscopy of a Leucine Zipper bZIP Complex" Biochemistry (2000) 39:548-556.

  • Weiss, M. A. and Narayana, N., "RNA Recognition by Arginine-Rich Peptide Motifs." Biopolymers (1999) 48:167-180.

  • Wang, B., Jones, D. N. M., Kaine, B. P., and Weiss, M. A., "High-Resolution Structure of an Archaeal Zinc Ribbon Defines a General Architectural Motif in Eukaryotic RNA Polymerases." Structure (1998) 6:555-569.

  • Su, L., Radek, J. R., Labeots, L. A., Hermanto, P., Chen, H., Nakagawa, S., Zhao, M., Kates, S., Hallenga, K., Chan, G., Weiss, M. A., "An RNA Enhancer in a Phage Transcriptional Antitermination Complex Functions as a Structural Switch." Genes & Development (1997) 11:2214-2226.

  • Labeots, L., and Weiss, M. A., "Electrostatics and Hydration at the Homeodomain-DNA Interface: Chemical Probes of an Interfacial Water Cavity." J. Molec. Biol. (1997) 269:113-128.