Structural and functional constraints in the evolution of protein families

Worth, Catherine L.; Gong, Sungsam; Blundell, Tom L.

doi:10.1038/nrm2762

Cited by 191 publications

(168 citation statements)

References 125 publications

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“…The biophysical constraints on IDP/IDR evolution [244] are quite different from those on folded protein evolution [12]. In fact, the accepted amino acid substitutions in IDPs/ IDRs resemble those in solvent-exposed loops and turns of globular proteins [244].…”

Section: Biophysical Constraints On Evolution Of Intrinsically Disordmentioning

confidence: 99%

“…A recent comprehensive review of numerous studies of mutants occurring in natural protein families and superfamilies shows clearly that amino acid substitutions are constrained differently-i.e. their viabilities vary-in different local environments as defined by the main-chain secondary structure, solvent accessibility and hydrogen bonding [12].…”

Section: Biophysical Consequences Of Protein Mutations 21 Mutationamentioning

confidence: 99%

“…Biophysics and polymer physics [12]). Secondary structures are conducive to tight tertiary packing as well.…”

Section: Applications Of Biophysics-based Models To Understand Proteimentioning

confidence: 99%

“…However, such trends capture only a tiny aspect of the many biophysical implications of mutations that can be important for the biological function of proteins. For instance, they often do not even consider the local structural environment of a given amino acid residue position such as backbone conformation and hydrogen bonding pattern that might constrain evolutionary choices [12].…”

Section: Introductionmentioning

confidence: 99%

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Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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The study of molecular evolution at the level of protein-coding genes often entails comparing large datasets of sequences to infer their evolutionary relationships. Despite the importance of a protein's structure and conformational dynamics to its function and thus its fitness, common phylogenetic methods embody minimal biophysical knowledge of proteins. To underscore the biophysical constraints on natural selection, we survey effects of protein mutations, highlighting the physical basis for marginal stability of natural globular proteins and how requirement for kinetic stability and avoidance of misfolding and misinteractions might have affected protein evolution. The biophysical underpinnings of these effects have been addressed by models with an explicit coarse-grained spatial representation of the polypeptide chain. Sequence-structure mappings based on such models are powerful conceptual tools that rationalize mutational robustness, evolvability, epistasis, promiscuous function performed by 'hidden' conformational states, resolution of adaptive conflicts and conformational switches in the evolution from one protein fold to another. Recently, protein biophysics has been applied to derive more accurate evolutionary accounts of sequence data. Methods have also been developed to exploit sequence-based evolutionary information to predict biophysical behaviours of proteins. The success of these approaches demonstrates a deep synergy between the fields of protein biophysics and protein evolution.

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Section: Biophysical Constraints On Evolution Of Intrinsically Disordmentioning

confidence: 99%

Section: Biophysical Consequences Of Protein Mutations 21 Mutationamentioning

confidence: 99%

“…Biophysics and polymer physics [12]). Secondary structures are conducive to tight tertiary packing as well.…”

Section: Applications Of Biophysics-based Models To Understand Proteimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biophysics of protein evolution and evolutionary protein biophysics

Sikosek

Chan

2014

J. R. Soc. Interface.

224

207

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“…The intimate relationship between a protein's structure and its function is a basic tenet of biology (Bagowski et al 2010;Worth et al 2009). Major advances in structural biology techniques over the past 20 or so years have led to the determination of the higher order structures of a wide range of globular proteins.…”

Section: Introductionmentioning

confidence: 99%

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Carver

Grosas

Ecroyd

et al. 2017

Cell Stress and Chaperones

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Small heat-shock proteins (sHsps), such as αB-crystallin, are one of the major classes of molecular chaperone proteins. In vivo, under conditions of cellular stress, sHsps are the principal defence proteins that prevent large-scale protein aggregation. Progress in determining the structure of sHsps has been significant recently, particularly in relation to the conserved, central and β-sheet structured α-crystallin domain (ACD). However, an understanding of the structure and functional roles of the N-and C-terminal flanking regions has proved elusive mainly because of their unstructured and dynamic nature. In this paper, we propose functional roles for both flanking regions, based around three properties: (i) they act in a localised crowding manner to regulate interactions with target proteins during chaperone action, (ii) they protect the ACD from deleterious amyloid fibril formation and (iii) the flexibility of these regions, particularly at the extreme C-terminus in mammalian sHsps, provides solubility for sHsps under chaperone and nonchaperone conditions. In the eye lens, these properties are highly relevant as the crystallin proteins, in particular the two sHsps αA-and αB-crystallin, are present at very high concentrations.

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Verstärkung der Bindung an das Proteinrückgrat – ein fruchtbares Konzept gegen die Arzneimittelresistenz von HIV

et al. 2012

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Die Entstehung von Arzneimittelresistenzen ist eines der grundlegenden Probleme der Medizin. Dass sich bei HIV/AIDS so schnell resistente HIV‐1‐Varianten einstellen, ist ein großes Hindernis für die modernen Therapien. Wichtige Zielmoleküle der derzeitigen antiretroviralen Therapien sind Inhibitoren der HIV‐1‐Protease. Das Virus entwickelt Resistenzen, wenn Mutationen die Inhibitorbindung des Enzyms verändern und somit die Effizienz mindern. Um diese Resistenzbildung zu vermeiden, haben wir Inhibitoren erforscht, die am aktiven Zentrum der Protease Wasserstoffbrücken zum Proteinrückgrat bilden. Weil sich die Geometrie am katalytischen Zentrum ohne Funktionsverlust nicht ändern kann, schränken solche Wechselwirkungen die Möglichkeiten der Protease zur Resistenzbildung erheblich ein. Hier diskutieren wir das enzymatische Strukturprinzip, auf dem unser Konzept der Rückgratbindung beruht. Besonderes Augenmerk richten wir auf die Anwendung des Konzepts in unseren jüngeren Arbeiten zu antiviralen Inhibitoren der HIV‐1‐Protease.

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Structural and functional constraints in the evolution of protein families

Cited by 191 publications

References 125 publications

Biophysics of protein evolution and evolutionary protein biophysics

Biophysics of protein evolution and evolutionary protein biophysics

The functional roles of the unstructured N- and C-terminal regions in αB-crystallin and other mammalian small heat-shock proteins

Verstärkung der Bindung an das Proteinrückgrat – ein fruchtbares Konzept gegen die Arzneimittelresistenz von HIV

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