Characterization of human variants in obesity-related SIM1 protein identifies a hot-spot for dimerization with the partner protein ARNT2
Date
2014
Authors
Sullivan, A.
Raimondo, A.
Schwab, T.
Bruning, J.
Froguel, P.
Farooqi, I.
Peet, D.
Whitelaw, M.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Biochemical Journal, 2014; 461(3):403-412
Statement of Responsibility
Adrienne E. Sullivan, Anne Raimondo, Tanja A. Schwab, John B. Bruning, Philippe Froguel, I. Sadaf Farooqi, Daniel J. Peet, Murray L. Whitelaw
Conference Name
Abstract
The bHLH (basic helix-loop-helix) PAS (Per/Arnt/Sim) transcription factor SIM1 (single-minded 1) is important for development and function of regions of the hypothalamus that regulate energy homoeostasis and the feeding response. Low-activity SIM1 variants have been identified in individuals with severe early-onset obesity, but the underlying molecular causes of impaired function are unknown. In the present study we assess a number of human SIM1 variants with reduced activity and determine that impaired function is frequently due to defects in dimerization with the essential partner protein ARNT2 (aryl hydrocarbon nuclear translocator 2). Equivalent variants generated in the highly related protein SIM2 (single-minded 2) produce near-identical impaired function and dimerization defects, indicating that these effects are not unique to the structure of SIM1. On the basis of these data, we predict that other select SIM1 and SIM2 variants reported in human genomic databases will also be deficient in activity, and identify two new low-activity SIM1 variants (V290E and V326F) present in the population. The cumulative data is used in homology modelling to make novel observations about the dimerization interface between the PAS domains of SIM1 and ARNT2, and to define a mutational 'hot-spot' in SIM1 that is critical for protein function.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
© The Authors Journal compilation © 2014 Biochemical Society