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Biochemistry Department - Primary Faculty

Michael A. Weiss, M.D., Ph.D., M.B.A.

Chairman of the Department of Biochemistry
Cowan-Blum Professor of Cancer Research and Professor of Biochemistry & Medicine (Endocrine Division)

Education

  • M.B.A. (2010) from the Case Western Reserve University Weatherhead School of Management
  • Ph.D.: in Biophysics (1986) from Harvard University
  • M.D.: (1985) from the Harvard Medical School/MIT Program in Health Sciences & Technology
  • A.B.: in Physics (1978) from Harvard College

Research Interests

Our investigations focus in two areas of molecular endocrinology: (a) insulin, insulin signaling, and diabetes mellitus; and (b) sex determination and infertility.

(a) Insulin. I began to study insulin in 1985 as a clinical fellow in medicine at the Brigham & Women’s Hospital. What began as a laboratory rotation during internship (with the encouragement of Drs. Marshall Wolf and Eugene Braunwald) led to a scientific adventure lasting almost 25 years. Studies, undertaken under the supervision of Prof. Martin Karplus (Department of Chemistry) and the late Dr. Leo J. Neuringer (Francis Bitter National Magnet Laboratory at MIT), were begun in partnership with fellow research resident Dr. Steve Shoelson. Steve (now professor of medicine and director of research at the Joslin Diabetes Center in Boston) had previously participated in the discovery of the classical insulinopathies as a student at the University of Chicago. Although insulin was considered well characterized even in 1985, the ensuing decades have uncovered one surprise after another, the fruits of an international effort to decipher the active structure of insulin, its mechanism of receptor binding, and conformational “life cycle.” In recent years, these new insights have enabled the invention of new insulin analogues with a wide variety of novel attributes.

My own scientific adventure with insulin has been enriched by a gifted group of students and fellows, colleagues Drs. Qing-xin Hua, S. Nakagawa, Zhu-Li Wan and Jonathan Whittaker, Prof. Nelson Phillips, and long-term collaborators Guy Dodson (York, UK), Pierre De Meyts (Copenhagen DK), Panno Katsoyannis (Mt. Sinai, NY), and Don Steiner (Chicago). Former and current CWRU graduate students engaged in studies of insulin are Dr. Bin Xu, Cheng-Yin Min, Dr. Kun Huang, and Vijay Pandyarajan.

(b) Sex Determination. Studies in sex determination seek to elucidate structure-function relationships in the HMG box of SRY and the DM motif, a novel Zn module. These domains bind in the minor groove of DNA. SRY, encoded by the mammalian Y chromosome, functions as the testis-determining factor to direct the differentiation of the bipotential gonad in embryogenesis. Insight into structure-function relationships is provided by a confluence of approaches, exploiting clinical mutations associated with chromosomal sex reversal to examine mechanisms of gene regulation in tissue culture. DM factors, broadly conserved among metazoans, function downstream of SRY in mammals wherein a family of homologues participate in spematogenesis (in males) and in the general specification of pattern (in both sexes). A model is provided by the Drosophila Doublesex factor, the prototype of the DM family. Sex-specific splicing of the Doublesex mRNA leads to male- and female-specific isoforms with distinct gene-regulatory properties. Structural studies of these isoforms provide a foundation for analysis of function in transgenic flies with application to the neurogenetic specification of courtship behaviors.

Studies of SRY were initiated twenty years ago in collaboration with Prof. Patricia K. Donahoe (Massachusetts General Hospital and Harvard Medical School). Ongoing studies of Doublesex represent a collaborative effort with Prof. Bruce Baker (Janelia Farm Research Campus of the Howard Hughes Medical Institute). These studies have been enriched by a series of gifted students, fellows, and colleagues, including Dr. Chih-Yen King (presently at the Institute of Molecular Biology in Taipei), Dr. Lingyang Zhu, Dr. Agnes Jancso, Dr. James Radek, Dr. Ging Chan, Dr. Laura Labeots, Dr. James Bayrer, Dr. Wei Zhang, and Prof. Nelson Phillips; collaborators Prof. Elisha Haas (Bar Ilan University), Prof. George Thomas, Jr. (University of Missouri), Prof. Stephen B. Kent (University of Chicago), and Prof. Peter Arvan and Assistant Prof. Ming Liu (University of Michigan); current CWRU graduate students Yen-Shan Chen and Joseph Racca; and many talented undergraduate students engaged in senior capstone projects at CWRU.

Selected References

  • Phillips N. B, Racca J.,  Chen Y-S., Singh R., Jancso-Radek A.,  Radek J. T., Wickramasinghe N. P., Haas E., and Weiss M. A.
    "Mammalian testis-determining factor SRY and the enigma of inherited human sex reversal: frustrated induced fit in a bent protein-DNA complex"
    J Biol Chem 286 (42): 36787-36807 (2011).

    Liu M., Haataja L., Wright J., Wickramasinghe N. P., Hua Q. X., Phillips N. F., Barbetti F., Weiss M. A., and Arvan P.
    “Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport”
    PLoS One 5 (10): e13333 (2010). Read article in PubMedCentral
  • Liu M., Hua Q. X., Hu S. Q., Jia W., Yang Y., Saith S. E., Whittaker J., Arvan P., and Weiss M. A.
    “Deciphering the hidden informational content of protein sequences: foldability of proinsulin hinges on a flexible arm that is dispensable in the mature hormone”
    J Biol Chem 285 (40): 30989-1001 (2010). Read article in PubMedCentral
  • Luisier S., Avital-Shmilovici M., Weiss M. A., and Kent S. B.
    “Total chemical synthesis of human proinsulin”
    Chem Commun (Camb) 46 (43): 8177-9 (2010).
  • Phillips N. B., Wan Z. L., Whittaker L., Hu S. Q., Huang K., Hua Q. X., Whittaker J., Ismail-Beigi F., and Weiss M. A.
    “Supramolecular protein engineering: design of zinc-stapled insulin hexamers as a long acting depot”
    J Biol Chem 285 (16): 11755-9 (2010). Read article in PubMedCentral
  • Smith B. J., Huang K., Kong G., Chan S. J., Nakagawa S., Menting J. G., Hu S. Q., Whittaker J., Steiner D. F., Katsoyannis P. G., Ward C. W., Weiss M. A., and Lawrence M. C.
    “Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists”
    Proc Natl Acad Sci U S A 107 (15): 6771-6 (2010). Read article in PubMedCentral
  • Sohma Y., Hua Q. X., Liu M., Phillips N. B., Hu S. Q., Whittaker J., Whittaker L. J., Ng A., Roberts C. T., Jr., Arvan P., Kent S. B., and Weiss M. A.
    “Contribution of residue B5 to the folding and function of insulin and IGF-I: constraints and fine-tuning in the evolution of a protein family
    J Biol Chem 285 (7): 5040-55 (2010). Read article in PubMedCentral
  • Sohma Y., Hua Q. X., Whittaker J., Weiss M. A., and Kent S. B.
    “Design and Folding of [Glu(A4)(O(beta)Thr(B30))]Insulin (‘Ester Insulin’), a Minimal Proinsulin Surrogate that Can Be Chemically Converted into Human Insulin”
    Angew Chem Int Ed Engl : (2010).
  • Yang Y., Hua Q. X., Liu J., Shimizu E. H., Choquette M. H., Mackin R. B., and Weiss M. A.
    “Solution structure of proinsulin: connecting domain flexibility and prohormone processing”
    J Biol Chem 285 (11): 7847-51 (2010). Read article in PubMedCentral
  • Yang Y., Petkova A., Huang K., Xu B., Hua Q. X., Ye I. J., Chu Y. C., Hu S. Q., Phillips N. B., Whittaker J., Ismail-Beigi F., Mackin R. B., Katsoyannis P. G., Tycko R., and Weiss M. A.
    “An Achilles’ heel in an amyloidogenic protein and its repair: insulin fibrillation and therapeutic design”
    J Biol Chem 285 (14): 10806-21 (2010). Read article in PubMedCentral
  • Hua Q. X., Xu B., Huang K., Hu S. Q., Nakagawa S., Jia W., Wang S., Whittaker J., Katsoyannis P. G., and Weiss M. A.
    “Enhancing the activity of a protein by stereospecific unfolding: conformational life cycle of insulin and its evolutionary origins”
    J Biol Chem 284 (21): 14586-96 (2009). Read article in PubMedCentral
  • Liu M., Wan Z. L., Chu Y. C., Aladdin H., Klaproth B., Choquette M., Hua Q. X., Mackin R. B., Rao J. S., De Meyts P., Katsoyannis P. G., Arvan P., and Weiss M. A.
    “Crystal structure of a ‘nonfoldable’ insulin: impaired folding efficiency despite native activity”
    J Biol Chem 284 (50): 35259-72 (2009). Read article in PubMedCentral
  • Narayana N. and Weiss M. A.
    “Crystallographic analysis of a sex-specific enhancer element: sequence-dependent DNA structure, hydration, and dynamics”
    J Mol Biol 385 (2): 469-90 (2009). Read article in PubMedCentral
  • Weiss M. A.
    “Proinsulin and the genetics of diabetes mellitus”
    J Biol Chem 284 (29): 19159-63 (2009). Read article in PubMedCentral
  • Xu B., Huang K., Chu Y. C., Hu S. Q., Nakagawa S., Wang S., Wang R. Y., Whittaker J., Katsoyannis P. G., and Weiss M. A.
    “Decoding the cryptic active conformation of a protein by synthetic photoscanning: insulin inserts a detachable arm between receptor domains”
    J Biol Chem 284 (21): 14597-608 (2009). Read article in PubMedCentral
  • Zhao M., Wan Z. L., Whittaker L., Xu B., Phillips N. B., Katsoyannis P. G., Ismail-Beigi F., Whittaker J., and Weiss M. A.
    “Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications”
    J Biol Chem 284 (46): 32178-87 (2009). Read article in PubMedCentral

 

Michael A. Weiss Faculty's publications at pubmed