Allostery and Epistasis: Emergent Properties of Anisotropic Networks

Campitelli, Paul; Ozkan, S. Banu

doi:10.3390/e22060667

Cited by 22 publications

(30 citation statements)

References 67 publications

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“…If we find the difference in the DCI values between two residue positions that are not directly interacting (i.e., in spatial contact), we get a better understanding of the dynamic allostery relationship between two residues. This difference, called DCI asymmetry, provides directionality to long-distance coupling, thereby suggesting a causal relationship In any given protein, every amino acid position has a unique network of direct, local interactions that give rise to a unique network of highly coupled partner positions [ 9 , 25 , 43 ] and heterogeneity in a 3-D network of interactions. Thus, for a particular pair of coupled amino acids ( i and j ), their unique network constraints differentiate the coupling of i to j from the coupling of j to i .…”

Section: Resultsmentioning

confidence: 99%

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

et al. 2022

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Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor fall in any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for pathogenesis. In this study, we present an analysis of 591 pathogenic missense variants in 144 human enzymes that suggests that allosteric dynamic coupling of mutated positions with known active sites is a plausible biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase) in which a vast majority of 94 sites harboring Gaucher disease-associated missense variants are located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling caused by missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.

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Section: Resultsmentioning

confidence: 99%

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

et al. 2022

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“…In this work, (i) substitutions at multiplex rheostat position 52 showed long-range effects on the dynamics of positions that directly contact DNA, and (ii) the set of linker rheostat positions showed coupling patterns that were distinct from linker toggle and neutral positions (72). Further, these types of dynamics computations have the potential to illuminate epistasis and allosteric regulation (75) and long-distance substitution effects on function (76). Protein dynamics have been shown to change during evolution ( e.g .…”

Section: Discussionmentioning

confidence: 99%

“Multiplex” rheostat positions cluster around allosterically critical regions of the lactose repressor protein

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Parente

Fenton

et al. 2020

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Amino acid variation at “rheostat” positions provides opportunity to modulate various aspects of protein function – such as binding affinity or allosteric coupling – across a wide range. Previously a subclass of “multiplex” rheostat positions was identified at which substitutions simultaneously modulated more than one functional parameter. Using the Miller laboratory’s dataset of ∼4000 variants of lactose repressor protein (LacI), we compared the structural properties of multiplex rheostat positions with (i) “single” rheostat positions that modulate only one functional parameter, (ii) “toggle” positions that follow textbook substitution rules, and (iii) “neutral” positions that tolerate any substitution without changing function. The combined rheostat classes comprised >40% of LacI positions, more than either toggle or neutral positions. Single rheostat positions were broadly distributed over the structure. Multiplex rheostat positions structurally overlapped with positions involved in allosteric regulation. When their phenotypic outcomes were interpreted within a thermodynamic framework, functional changes at multiplex positions were uncorrelated. This suggests that substitutions lead to complex changes in the underlying molecular biophysics. Bivariable and multivariable analyses of evolutionary signals within multiple sequence alignments could not differentiate single and multiplex rheostat positions. Phylogenetic analyses – such as ConSurf – could distinguish rheostats from toggle and neutral positions. Multivariable analyses could also identify a subset of neutral positions with high probability. Taken together, these results suggest that detailed understanding of the underlying molecular biophysics, likely including protein dynamics, will be required to discriminate single and multiplex rheostat positions from each other and to predict substitution outcomes at these sites.

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“…In any given protein, every amino acid position has a unique network of direct, local interactions that give rise to a unique network of highly coupled partner positions [9,24,42] and heteronegeity in a 3-D network of interactions. Thus, for a particular pair of coupled amino acids (i and j), their unique network constraints differentiate the coupling of i to j from the coupling of j to i.…”

Section: Mutations At Distal Sites Dynamically-coupled To the Active Site Alter Long-range Communicationmentioning

confidence: 99%

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

Ose

Butler

Kumar

et al. 2021

Preprint

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Many pathogenic missense mutations are found in protein positions that are neither well-conserved nor belong to any known functional domains. Consequently, we lack any mechanistic underpinning of dysfunction caused by such mutations. We explored the disruption of allosteric dynamic coupling between these positions and the known functional sites as a possible mechanism for such mutations. In this study, we present an analysis of 144 human enzymes containing 591 pathogenic missense variants, in which allosteric dynamic coupling of mutated positions with known active sites provides insights into a primary biophysical mechanism and evidence of their functional importance. We illustrate this mechanism in a case study of β-Glucocerebrosidase (GCase), which contains 94 Gaucher disease-associated missense variants located some distance away from the active site. An analysis of the conformational dynamics of GCase suggests that mutations on these distal sites cause changes in the flexibility of active site residues despite their distance, indicating a dynamic communication network throughout the protein. The disruption of the long-distance dynamic coupling due to the presence of missense mutations may provide a plausible general mechanistic explanation for biological dysfunction and disease.

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Allostery and Epistasis: Emergent Properties of Anisotropic Networks

Cited by 22 publications

References 67 publications

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

“Multiplex” rheostat positions cluster around allosterically critical regions of the lactose repressor protein

Dynamic coupling of residues within proteins as a mechanistic foundation of many enigmatic pathogenic missense variants

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