Faculty Collaboration Database

Diabetes mutations delineate an atypical POU domain in HNF-1alpha. Mol Cell 2002 Nov;10(5):1129-37

Date

11/28/2002

Pubmed ID

12453420

DOI

10.1016/s1097-2765(02)00704-9

Scopus ID

2-s2.0-0036862511 (requires institutional sign-in at Scopus site)   89 Citations

Abstract

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.

Author List

Chi YI, Frantz JD, Oh BC, Hansen L, Dhe-Paganon S, Shoelson SE

Author

Young-In Chi PhD Assistant Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amino Acid Sequence
Base Sequence
Codon
Crystallography, X-Ray
DNA
DNA-Binding Proteins
Diabetes Mellitus
Hepatocyte Nuclear Factor 1
Hepatocyte Nuclear Factor 1-alpha
Hepatocyte Nuclear Factor 1-beta
Humans
Models, Molecular
Molecular Sequence Data
Mutation
Mutation, Missense
Nuclear Proteins
POU Domain Factors
Promoter Regions, Genetic
Protein Binding
Protein Structure, Tertiary
Recombinant Proteins
Sequence Homology, Amino Acid
Transcription Factors
Transcription, Genetic
X-Ray Diffraction