scholarly journals Selection for cooperativity causes epistasis predominately between native contacts and enables epistasis-based structure reconstruction

2021 ◽  
Vol 118 (16) ◽  
pp. e2010057118
Author(s):  
R. Charlotte Eccleston ◽  
David D. Pollock ◽  
Richard A. Goldstein
Keyword(s):  
Protein Structure ◽  
Native Structure ◽  
Guanine Nucleotide Binding Protein ◽  
Epistatic Interactions ◽  
Intermediate States ◽  
Predict Protein Structure ◽  
Selection For ◽  
Guanine Nucleotide Binding ◽  
Energetic Interactions ◽  
Protein Gb1

Epistasis and cooperativity of folding both result from networks of energetic interactions in proteins. Epistasis results from energetic interactions among mutants, whereas cooperativity results from energetic interactions during folding that reduce the presence of intermediate states. The two concepts seem intuitively related, but it is unknown how they are related, particularly in terms of selection. To investigate their relationship, we simulated protein evolution under selection for cooperativity and separately under selection for epistasis. Strong selection for cooperativity created strong epistasis between contacts in the native structure but weakened epistasis between nonnative contacts. In contrast, selection for epistasis increased epistasis in both native and nonnative contacts and reduced cooperativity. Because epistasis can be used to predict protein structure only if it preferentially occurs in native contacts, this result indicates that selection for cooperativity may be key for predicting structure using epistasis. To evaluate this inference, we simulated the evolution of guanine nucleotide-binding protein (GB1) with and without cooperativity. With cooperativity, strong epistatic interactions clearly map out the native GB1 structure, while allowing the presence of intermediate states (low cooperativity) obscured the structure. This indicates that using epistasis measurements to reconstruct protein structure may be inappropriate for proteins with stable intermediates.

scholarly journals Selection for Protein Stability Enriches for Epistatic Interactions

Genes ◽  
2018 ◽  
Vol 9 (9) ◽  
pp. 423 ◽  
Author(s):  
Anna Posfai ◽  
Juannan Zhou ◽  
Joshua Plotkin ◽  
Justin Kinney ◽  
David McCandlish
Keyword(s):  
Free Energy ◽  
Protein Sequence ◽  
Native Structure ◽  
Evolutionary Time ◽  
Epistatic Interactions ◽  
Abundant Evidence ◽  
Additive Contribution ◽  
Selection For ◽  
Protein Sequence Space ◽  
Folding Free Energy

A now classical argument for the marginal thermodynamic stability of proteins explains the distribution of observed protein stabilities as a consequence of an entropic pull in protein sequence space. In particular, most sequences that are sufficiently stable to fold will have stabilities near the folding threshold. Here, we extend this argument to consider its predictions for epistatic interactions for the effects of mutations on the free energy of folding. Although there is abundant evidence to indicate that the effects of mutations on the free energy of folding are nearly additive and conserved over evolutionary time, we show that these observations are compatible with the hypothesis that a non-additive contribution to the folding free energy is essential for observed proteins to maintain their native structure. In particular, through both simulations and analytical results, we show that even very small departures from additivity are sufficient to drive this effect.

scholarly journals Selection for protein stability enriches for epistatic interactions

2018 ◽  
Author(s):  
Anna Posfai ◽  
Juannan Zhou ◽  
Joshua B. Plotkin ◽  
Justin B. Kinney ◽  
David M. McCandlish
Keyword(s):  
Free Energy ◽  
Protein Sequence ◽  
Native Structure ◽  
Evolutionary Time ◽  
Epistatic Interactions ◽  
Abundant Evidence ◽  
Additive Contribution ◽  
Selection For ◽  
Protein Sequence Space ◽  
Folding Free Energy

AbstractA now classical argument for the marginal thermodynamic stability of proteins explains the distribution of observed protein stabilities as a consequence of an entropic pull in protein sequence space. In particular, most sequences that are sufficiently stable to fold will have stabilities near the folding threshold. Here we extend this argument to consider its predictions for epistatic interactions for the effects of mutations on the free energy of folding. Although there is abundant evidence to indicate that the effects of mutations on the free energy of folding are nearly additive and conserved over evolutionary time, we show that these observations are compatible with the hypothesis that a non-additive contribution to the folding free energy is essential for observed proteins to maintain their native structure. In particular through both simulations and analytical results, we show that even very small departures from additivity are sufficient to drive this effect.

Mapping the Heart

2010 ◽  
Vol 18 (4) ◽  
pp. 6-8
Author(s):  
Stephen W. Carmichael
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Cardiac Muscle Cells ◽  
Guanine Nucleotide Binding Protein ◽  
The Common ◽  
Guanine Nucleotide Binding ◽  
First Time ◽  
G Protein Coupled

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

scholarly journals A novel missense variant of the GNAI3 gene and recognisable morphological characteristics of the mandibula in ARCND1

2021 ◽  
Author(s):  
Kumiko Yanagi ◽  
Noriko Morimoto ◽  
Manami Iso ◽  
Yukimi Abe ◽  
Kohji Okamura ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Morphological Characteristics ◽  
Missense Variant ◽  
Nucleotide Binding ◽  
Sequencing Analysis ◽  
Guanine Nucleotide ◽  
Guanine Nucleotide Binding Protein ◽  
Computer Tomography Scan ◽  
Novel Variant ◽  
Guanine Nucleotide Binding

AbstractAuriculocondylar syndrome (ARCND) is an autosomal monogenic disorder characterised by external ear abnormalities and micrognathia due to hypoplasia of the mandibular rami, condyle and coronoid process. Genetically, three subtypes of ARCND (ARCND1, ARCND2 and ARCND3) have been reported. To date, five pathogenic variants of GNAI3 have been reported in ARCND1 patients. Here, we report a novel variant of GNAI3 (NM_006496:c.807C>A:p.(Asn269Lys)) in a Japanese girl with micrognathia using trio-based whole exome sequencing analysis. The GNAI3 gene encodes a heterotrimeric guanine nucleotide-binding protein. The novel variant locates the guanine nucleotide-binding site, and the substitution was predicted to interfere with guanine nucleotide-binding by in silico structural analysis. Three-dimensional computer tomography scan, or cephalogram, displayed severely hypoplastic mandibular rami and fusion to the medial and lateral pterygoid plates, which have been recognised in other ARCND1 patients, but have not been described in ARCND2 and ARCND3, suggesting that these may be distinguishable features in ARCND1.

Sign in / Sign up

Export Citation Format

Share Document