Diabetes mutations delineate an atypical POU domain in HNF-1α

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Abstract

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.

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Chi, Y. I., Frantz, J. D., Oh, B. C., Hansen, L., Dhe-Paganon, S., & Shoelson, S. E. (2002). Diabetes mutations delineate an atypical POU domain in HNF-1α. Molecular Cell, 10(5), 1129–1137. https://doi.org/10.1016/S1097-2765(02)00704-9

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