Diabetes Mutations Delineate an Atypical POU Domain in HNF-1alpha

• Autores: Byung-Chul Oh, J. Daniel Frantz, Young-in Chi
• Localización: Molecular cell, ISSN 1097-2765, Nº 10, 2002, págs. 1129-1138
• Idioma: inglés
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• Resumen

  • Mutations in Hnf-1α are the most common Mendelian cause of diabetes mellitus. To elucidate the molecular function of a mutational hotspot, we cocrystallized human HNF-1α 83–279 with a high-affinity promoter and solved the structure of the complex. Two identical protein molecules are bound to the promoter. Each contains a homeodomain and a second domain structurally similar to POU-specific domains that was not predicted on the basis of amino acid sequence. Atypical elements in both domains create a stable interface that further distinguishes HNF-1α from other flexible POU-homeodomain proteins. The numerous diabetes-causing mutations in HNF-1α thus identified a previously unrecognized POU domain which was used as a search model to identify additional POU domain proteins in sequence databases.