Conformational diversity and the emergence of sequence signatures during evolution

Parisi, Gustavo; Zea, Diego Javier; Monzón, Alexander Miguel; Marino-Buslje, Cristina

doi:10.1016/j.sbi.2015.02.005

Cited by 34 publications

(31 citation statements)

References 56 publications

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“…In conclusion, protein structure and evolutionary fitness are closely linked (62). Selection pressure leads to evolutionary consequences, wherein individual changes at hot spot residues can select for a survival benefit or disadvantage.…”

Section: Discussionmentioning

confidence: 97%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCEViruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis. Human adenoviruses (HAdVs) are major causes of respiratory disease, gastroenteritis, and keratoconjunctivitis (1-4). HAdV infections are also a major concern in immunocompromised hosts, with fatality rates as high as 55% (5). There are 72 HAdVs currently genotyped in GenBank, which are classified into seven species (HAdV-A to -G) as determined by whole-genome analysis. The majority (n ϭ 47) belong to HAdV-D, including types 8, 37, 53, 54, 56, and 64 (6-12). Each of these has been associated with epidemic keratoconjunctivitis (EKC), a highly contagious ocular surface infection (13). HAdV-D evolves by homologous recombination within genes encoding the major HAdV capsid proteins (14). For example, type 64 (previously typed as 19a) is a recombinant with types 19, 22, and 37 in the hexon, penton ba...

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Section: Discussionmentioning

confidence: 97%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

J Virol

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“…). Conformational diversity is a key concept to understand many processes and mechanisms in protein function, such as enzyme catalysis, promiscuity in protein interactions, protein‐protein recognition, signal transduction, mechanisms of disease‐related mutations, immune escape, the origin of neurodegenerative diseases, protein evolutionary rates, conformer‐specific substitution patterns, the origins of new biological functions, molecular motors, and co‐evolutionary measurements between residues (for a recent review please see). Furthermore, we have recently shown that the distribution of CD in a large dataset of proteins, with experimentally determined CD (approximately 5000 proteins), results in three main groups of proteins with different structure‐function relationships .…”

Section: Discussionmentioning

confidence: 99%

“…A wide range of structural differences among conformers can be observed by comparing structures of the same protein obtained under different crystallization conditions. These differences result from the relative movements of large domains, secondary and tertiary element rearrangements, and loop movements, which overall can produce a conformational diversity up to 4–5 Å of RMSD . Even up to 15–20 Å can be observed, depending on the structural alignment algorithm used to calculate the RMSD .…”

Section: Introductionmentioning

confidence: 99%

Homology modeling in a dynamical world

et al. 2017

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A key concept in template-based modeling (TBM) is the high correlation between sequence and structural divergence, with the practical consequence that homologous proteins that are similar at the sequence level will also be similar at the structural level. However, conformational diversity of the native state will reduce the correlation between structural and sequence divergence, because structural variation can appear without sequence diversity. In this work, we explore the impact that conformational diversity has on the relationship between structural and sequence divergence. We find that the extent of conformational diversity can be as high as the maximum structural divergence among families. Also, as expected, conformational diversity impairs the well-established correlation between sequence and structural divergence, which is nosier than previously suggested. However, we found that this noise can be resolved using a priori information coming from the structure-function relationship. We show that protein families with low conformational diversity show a well-correlated relationship between sequence and structural divergence, which is severely reduced in proteins with larger conformational diversity. This lack of correlation could impair TBM results in highly dynamical proteins. Finally, we also find that the presence of order/disorder can provide useful beforehand information for better TBM performance.

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“…Accounting for protein flexibility is essential to better predict and understand protein behaviour, including in particular molecular recognition. Conformational entropy is one of the main driving forces of protein binding and is one of the major determinants of protein evolution . As a consequence, flexibility is a key protein property, especially for regulatory proteins, and it is relevant for many human diseases .…”

Section: Introductionmentioning

confidence: 99%

A superposition free method for protein conformational ensemble analyses and local clustering based on a differential geometry representation of backbone

et al. 2019

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Here a differential geometry (DG) representation of protein backbone is explored on the analyses of protein conformational ensembles. The protein backbone is described by curvature, κ, and torsion, τ, values per residue and we propose 1) a new dissimilarity and protein flexibility measurement and 2) a local conformational clustering method. The methods were applied to Ubiquitin and c‐Myb‐KIX protein conformational ensembles and results show that κ\τ metric space allows to properly judge protein flexibility by avoiding the superposition problem. The dmax measurement presents equally good or superior results when compared to RMSF, especially for the intrinsically unstructured protein. The clustering method is unique as it relates protein global to local dynamics by providing a global clustering solutions per residue. The methods proposed can be especially useful to the analyses of highly flexible proteins. The software written for the analyses presented here is available at https://github.com/AMarinhoSN/FleXgeo for academic usage only.

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Conformational diversity and the emergence of sequence signatures during evolution

Cited by 34 publications

References 56 publications

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Homology modeling in a dynamical world

A superposition free method for protein conformational ensemble analyses and local clustering based on a differential geometry representation of backbone

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