Michael Weiss, Ph.D. Professor and Chairman of Biochemistry Department E-mail: weiss@biocserver.bioc.cwru.edu Telephone: (216) 368-5991 FAX: (216) 368-3419

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 Publications:

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 & Development 17: in press.
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., in press.
Hua, Qing-Xin; Jia, Wenhua; Frank, Bruce H.; Phillips, Nelson F. B.; Weiss, Michael A.
A Protein Caught in a Kinetic Trap: Structures and Stabilities of Insulin Disulfide Isomers.
Biochemistry 2002 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-isoleucine^A2 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 Protin 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
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
Hua, Q. X., Zhao, M., Narayana, N., Nakagawa, S. H., Jia, W., and Weiss, M. A.,
"Diabetes-associatedMutations in a b-Cell Transcription Factor Destabilize an Anti-Parallel "Mini-Zipper."
Proc. Natl. Acad. Sci. USA (2000) 97:1999-2004.
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.
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.
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.
Jacoby, E., Hua, Q. X., Stern, A., Frank, B. H., and Weiss, M. A.,
"Structure and Dynamics of a Protein Assembly: 1H-NMR Studies of the 36 kD R6 Insulin Hexamer."
J. Molec. Biol. (1996) 258:136-157.
Hua, Q. X., Gozani, S., Chance, R. E., Hoffmann, J. A., Frank, B. H., and Weiss, M. A.,
"Structure of a Protein in a Kinetic Trap."
Nature Struct. Biol. (1995) 2:129-138.
Haqq, C. M., King, C.-Y., Ukiyama, E., Haqq, T. N., Falsalfi, S., Donahoe, P. K., and Weiss, M. A.,
"Molecular Basis of Mammalian Sexual Determination: Activation of MIS by SRY."
Science (1994) 266:1494-1500.
King, C. Y. and Weiss, M. A.,
"The SRY HMG-Box Recognizes DNA by Partial Intercalation in the Minor Groove: a Topological Mechanism of Sequence Specificity."
Proc. Natl. Acad. Sci. U.S.A. (1993) 90:11990-11994.
Qian, X., Jeon, H., Agarwal, K., and Weiss, M. A.,
"The Zn Ribbon: Structure of the Nucleic-Acid Binding Domain of Elongation Factor TFIIS."
Nature (1993) 365:277-279.
Hua, Q. X., Shoelson, S. E., Kochoyan, M., and Weiss, M. A.,
"Receptor Binding Redefined by a Structural Switch in the Solution Structure of a Mutant Human Insulin."
Nature (1991) 354:238-241.
Weiss, M. A., Ellenberger, T. E., Wobbe, C. R., Harrison, S. C., and Struhl, K.,
"Folding Transition in the DNA-Binding Domain of GCN4 on Specific DNA Binding to DNA."
Nature (1990) 347:575-578.

Academic Experience

In 1985, Weiss earned his M.D. degree, summa cum laude, from the Harvard Medical School, and, in 1986, the Ph.D. degree in biophysics from Harvard University. He then completed a residency in internal medicine and a fellowship in medicine at Brigham and Women's Hospital, Boston, from 1985 to 1988. He is board certified in internal medicine.
He has received numerous honors and awards, including the Fletcher Scholars Awarrd in Cancer Research and the Harvard Medical School Soma Weiss Research Award. In 1994, he was named a Lucille Markey Scholar and Bane Scholar at the University of Chicago and Established Investigator of the American Heart Association. He was also appointed to the White House Comission en Presidential Scholars.