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

被引:87
作者
Chi, YI
Frantz, JD
Oh, BC
Hansen, L
Dhe-Paganon, S
Shoelson, SE [1 ]
机构
[1] Harvard Univ, Sch Med, Joslin Diabet Ctr, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA
关键词
D O I
10.1016/S1097-2765(02)00704-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Mutations in Hnf-1alpha are the most common Mendelian cause of diabetes mellitus. To elucidate the molecular function of a mutational hotspot, we cocrystallized human HNF-1alpha 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-1alpha from other flexible POU-homeodomain proteins. The numerous diabetes causing mutations in HNF-1alpha thus identified a previously unrecognized POU domain which was used as a search model to identify additional POU domain proteins in sequence databases.
引用
收藏
页码:1129 / 1137
页数:9
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