Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain
Single-minded homologue 1 (SIM1) is a transcription factor with numerous different physiological and developmental functions. SIM1 is a member of the class I basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factor family, that includes several other conserved proteins, including the hypo...
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doaj-fd9cee8ddfeb498d9b1ad6472beae06f2020-11-25T03:24:35ZengMDPI AGBiomolecules2218-273X2020-09-01101314131410.3390/biom10091314Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation DomainMathew A. Coban0Patrick R. Blackburn1Murray L. Whitelaw2Mieke M. van Haelst3Paldeep S. Atwal4Thomas R. Caulfield5Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USADepartment of Molecular and Cellular Biology, University of Adelaide, Adelaide SA 5000, AustraliaDepartment of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsCenter for Individualized Medicine, Mayo Clinic, Jacksonville, FL 32224, USADepartment of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USASingle-minded homologue 1 (SIM1) is a transcription factor with numerous different physiological and developmental functions. SIM1 is a member of the class I basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factor family, that includes several other conserved proteins, including the hypoxia-inducible factors, aryl hydrocarbon receptor, neuronal PAS proteins, and the CLOCK circadian regulator. Recent studies of HIF-a-ARNT and CLOCK-BMAL1 protein complexes have revealed the organization of their bHLH, PASA, and PASB domains and provided insight into how these heterodimeric protein complexes form; however, experimental structures for SIM1 have been lacking. Here, we describe the first full-length atomic structural model for human SIM1 with its binding partner ARNT in a heterodimeric complex and analyze several pathogenic variants utilizing state-of-the-art simulations and algorithms. Using local and global positional deviation metrics, deductions to the structural basis for the individual mutants are addressed in terms of the deleterious structural reorganizations that could alter protein function. We propose new experiments to probe these hypotheses and examine an interesting SIM1 dynamic behavior. The conformational dynamics demonstrates conformational changes on local and global regions that represent a mechanism for dysfunction in variants presented. In addition, we used our ab initio hybrid model for further prediction of variant hotspots that can be engineered to test for counter variant (restoration of wild-type function) or basic research probe.https://www.mdpi.com/2218-273X/10/9/1314single-minded homologue 1enhanced molecular dynamicscomputational modelingvariants of uncertain significancePrader-Willi-like syndrome |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mathew A. Coban Patrick R. Blackburn Murray L. Whitelaw Mieke M. van Haelst Paldeep S. Atwal Thomas R. Caulfield |
spellingShingle |
Mathew A. Coban Patrick R. Blackburn Murray L. Whitelaw Mieke M. van Haelst Paldeep S. Atwal Thomas R. Caulfield Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain Biomolecules single-minded homologue 1 enhanced molecular dynamics computational modeling variants of uncertain significance Prader-Willi-like syndrome |
author_facet |
Mathew A. Coban Patrick R. Blackburn Murray L. Whitelaw Mieke M. van Haelst Paldeep S. Atwal Thomas R. Caulfield |
author_sort |
Mathew A. Coban |
title |
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain |
title_short |
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain |
title_full |
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain |
title_fullStr |
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain |
title_full_unstemmed |
Structural Models for the Dynamic Effects of Loss-of-Function Variants in the Human SIM1 Protein Transcriptional Activation Domain |
title_sort |
structural models for the dynamic effects of loss-of-function variants in the human sim1 protein transcriptional activation domain |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2020-09-01 |
description |
Single-minded homologue 1 (SIM1) is a transcription factor with numerous different physiological and developmental functions. SIM1 is a member of the class I basic helix-loop-helix-PER-ARNT-SIM (bHLH–PAS) transcription factor family, that includes several other conserved proteins, including the hypoxia-inducible factors, aryl hydrocarbon receptor, neuronal PAS proteins, and the CLOCK circadian regulator. Recent studies of HIF-a-ARNT and CLOCK-BMAL1 protein complexes have revealed the organization of their bHLH, PASA, and PASB domains and provided insight into how these heterodimeric protein complexes form; however, experimental structures for SIM1 have been lacking. Here, we describe the first full-length atomic structural model for human SIM1 with its binding partner ARNT in a heterodimeric complex and analyze several pathogenic variants utilizing state-of-the-art simulations and algorithms. Using local and global positional deviation metrics, deductions to the structural basis for the individual mutants are addressed in terms of the deleterious structural reorganizations that could alter protein function. We propose new experiments to probe these hypotheses and examine an interesting SIM1 dynamic behavior. The conformational dynamics demonstrates conformational changes on local and global regions that represent a mechanism for dysfunction in variants presented. In addition, we used our ab initio hybrid model for further prediction of variant hotspots that can be engineered to test for counter variant (restoration of wild-type function) or basic research probe. |
topic |
single-minded homologue 1 enhanced molecular dynamics computational modeling variants of uncertain significance Prader-Willi-like syndrome |
url |
https://www.mdpi.com/2218-273X/10/9/1314 |
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