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.
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August 2014
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Research Article|
July 10 2014
Characterization of human variants in obesity-related SIM1 protein identifies a hot-spot for dimerization with the partner protein ARNT2
Adrienne E. Sullivan;
Adrienne E. Sullivan
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
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Anne Raimondo;
Anne Raimondo
1
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
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Tanja A. Schwab;
Tanja A. Schwab
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
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John B. Bruning;
John B. Bruning
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
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Philippe Froguel;
Philippe Froguel
†CNRS-UMR8199, Lille Pasteur Institute, 59010 Lille, France
‡Lille Nord de France University, 59044 Lille, France
§Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London W12 ONN, U.K.
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I. Sadaf Farooqi;
I. Sadaf Farooqi
∥University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, U.K.
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Daniel J. Peet;
Daniel J. Peet
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
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Murray L. Whitelaw
Murray L. Whitelaw
2
*School of Molecular and Biomedical Science (Biochemistry) and Centre for Molecular Pathology, University of Adelaide, Adelaide 5005, South Australia, Australia
2To whom correspondence should be addressed (email murray.whitelaw@adelaide.edu.au).
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Publisher: Portland Press Ltd
Received:
December 09 2013
Revision Received:
April 15 2014
Accepted:
May 12 2014
Accepted Manuscript online:
May 12 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 461 (3): 403–412.
Article history
Received:
December 09 2013
Revision Received:
April 15 2014
Accepted:
May 12 2014
Accepted Manuscript online:
May 12 2014
Citation
Adrienne E. Sullivan, Anne Raimondo, Tanja A. Schwab, John B. Bruning, Philippe Froguel, I. Sadaf Farooqi, Daniel J. Peet, Murray L. Whitelaw; Characterization of human variants in obesity-related SIM1 protein identifies a hot-spot for dimerization with the partner protein ARNT2. Biochem J 1 August 2014; 461 (3): 403–412. doi: https://doi.org/10.1042/BJ20131618
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