Steven E. Shoelson, MD, PhDJoslin Diabetes Center
One Joslin Place
Boston, MA 02215
tel: (617) 732-2528; Fax: (617) 735-1970
Our studies in structural biology focus on diabetes. Targets are subdivided into (1) genetic causes of diabetes, including MODY, lipodystrophy and obesity, (2) potential mediators of insulin resistance, and (3) autoantigens in type 1 diabetes. Examples of recently solved structures include:
HNF-1a. Mutations in the MODY3 gene, the most common monogenic cause of diabetes, map to the transcription factor HNF-1a. The structure of HNF1a bound to DNA, which we have solved at 2.3 å resolution, reveals a heretofore unidentified POU-homeodomain (HNF1a lacks sequence homology with Pit1, Oct or Unc). Over 40 distinct mutations map to the crystallized region; those that perturb DNA binding, protein-protein interactions, nuclear localization, protein stability, and dimerization are readily discriminated by their structure.
Lamin A/C. We have also solved structures at 1.4 å resolution of the nuclear lamin A/C globular tail. This region is mutated in familial partial lipodystrophy (FPLD), whereas missense mutations throughout lamin A/C may cause autosomal recessive forms of muscular dystrophy (Emery-Dreifuss, Limb-Girdle and familial cardiac conduction disease). The tail forms a nine-stranded b sandwich resembling an immunoglobulin fold. FPLD mutations map to a discrete surface patch, whereas muscular dystrophy mutations are within the domain's hydrophobic core. The structure is thus helping to resolve why clinical phenotypes of some mutations are manifested in fat while others are in muscle.
Autoantigens. Humoral and cellular autoimmune responses are mounted against an intracellular domain of IA-2, and antibodies and HLA-DR4 positive T cells against IA-2 are present in the majority of patients with newly-diagnosed type 1 diabetes. The structure at 2.4 å resolution reveals a single protein tyrosine phosphatase-like domain, which is helping to rationalize both catalytic and antigenic properties of IA-2.
Hof P, Pluskey S, Dhe-Paganon S, Eck MJ, and Shoelson SE (1998). Crystal structure of the tyrosine phosphatase SHP-2. Cell. 92, 441-450.
Dhe-Paganon S, Ottinger E, Nolte R, Eck MJ, and Shoelson SE (1999). Crystal structure of the PH-PTB targeting region of IRS-1. Proc.Natl.Acad.Sci.U.S.A. 96, 8378-8383.
Dhe-Paganon, S., Shigeta, R., Chi, Y.I., Ristow, M., and Shoelson, S.E. (2000). Crystal structure of human Frataxin. J. Biol. Chem. 275, 30753-30756.
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