scholarly journals Evidence of evolutionary selection for cotranslational folding

2017 ◽  
Vol 114 (43) ◽  
pp. 11434-11439 ◽  
Author(s):  
William M. Jacobs ◽  
Eugene I. Shakhnovich

Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from cotranslational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for cotranslational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with cotranslational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of cotranslational folding account for the majority of these loci across more than 500 Escherichia coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.

2017 ◽  
Author(s):  
William M. Jacobs ◽  
Eugene I. Shakhnovich

Recent experiments and simulations have demonstrated that proteins can fold on the ribosome. However, the extent and generality of fitness effects resulting from co-translational folding remain open questions. Here we report a genome-wide analysis that uncovers evidence of evolutionary selection for co-translational folding. We describe a robust statistical approach to identify loci within genes that are both significantly enriched in slowly translated codons and evolutionarily conserved. Surprisingly, we find that domain boundaries can explain only a small fraction of these conserved loci. Instead, we propose that regions enriched in slowly translated codons are associated with co-translational folding intermediates, which may be smaller than a single domain. We show that the intermediates predicted by a native-centric model of co-translational folding account for the majority of these loci across more than 500 E. coli proteins. By making a direct connection to protein folding, this analysis provides strong evidence that many synonymous substitutions have been selected to optimize translation rates at specific locations within genes. More generally, our results indicate that kinetics, and not just thermodynamics, can significantly alter the efficiency of self-assembly in a biological context.


Genetics ◽  
2013 ◽  
Vol 196 (3) ◽  
pp. 829-840 ◽  
Author(s):  
Timothy M. Beissinger ◽  
Candice N. Hirsch ◽  
Brieanne Vaillancourt ◽  
Shweta Deshpande ◽  
Kerrie Barry ◽  
...  

2021 ◽  
Vol 7 (24) ◽  
pp. eabg3097
Author(s):  
Bo Zhao ◽  
Yanpeng Xi ◽  
Junghyun Kim ◽  
Sibum Sung

Chromatin structure is critical for gene expression and many other cellular processes. In Arabidopsis thaliana, the floral repressor FLC adopts a self-loop chromatin structure via bridging of its flanking regions. This local gene loop is necessary for active FLC expression. However, the molecular mechanism underlying the formation of this class of gene loops is unknown. Here, we report the characterization of a group of linker histone-like proteins, named the GH1-HMGA family in Arabidopsis, which act as chromatin architecture modulators. We demonstrate that these family members redundantly promote the floral transition through the repression of FLC. A genome-wide study revealed that this family preferentially binds to the 5′ and 3′ ends of gene bodies. The loss of this binding increases FLC expression by stabilizing the FLC 5′ to 3′ gene looping. Our study provides mechanistic insights into how a family of evolutionarily conserved proteins regulates the formation of local gene loops.


2020 ◽  
Vol 10 (6) ◽  
pp. 2057-2068 ◽  
Author(s):  
Jessica R. Eisenstatt ◽  
Lars Boeckmann ◽  
Wei-Chun Au ◽  
Valerie Garcia ◽  
Levi Bursch ◽  
...  

The evolutionarily conserved centromeric histone H3 variant (Cse4 in budding yeast, CENP-A in humans) is essential for faithful chromosome segregation. Mislocalization of CENP-A to non-centromeric chromatin contributes to chromosomal instability (CIN) in yeast, fly, and human cells and CENP-A is highly expressed and mislocalized in cancers. Defining mechanisms that prevent mislocalization of CENP-A is an area of active investigation. Ubiquitin-mediated proteolysis of overexpressed Cse4 (GALCSE4) by E3 ubiquitin ligases such as Psh1 prevents mislocalization of Cse4, and psh1Δ strains display synthetic dosage lethality (SDL) with GALCSE4. We previously performed a genome-wide screen and identified five alleles of CDC7 and DBF4 that encode the Dbf4-dependent kinase (DDK) complex, which regulates DNA replication initiation, among the top twelve hits that displayed SDL with GALCSE4. We determined that cdc7-7 strains exhibit defects in ubiquitin-mediated proteolysis of Cse4 and show mislocalization of Cse4. Mutation of MCM5 (mcm5-bob1) bypasses the requirement of Cdc7 for replication initiation and rescues replication defects in a cdc7-7 strain. We determined that mcm5-bob1 does not rescue the SDL and defects in proteolysis of GALCSE4 in a cdc7-7 strain, suggesting a DNA replication-independent role for Cdc7 in Cse4 proteolysis. The SDL phenotype, defects in ubiquitin-mediated proteolysis, and the mislocalization pattern of Cse4 in a cdc7-7 psh1Δ strain were similar to that of cdc7-7 and psh1Δ strains, suggesting that Cdc7 regulates Cse4 in a pathway that overlaps with Psh1. Our results define a DNA replication initiation-independent role of DDK as a regulator of Psh1-mediated proteolysis of Cse4 to prevent mislocalization of Cse4.


2016 ◽  
Vol 113 (46) ◽  
pp. 13109-13113 ◽  
Author(s):  
Igor B. Rogozin ◽  
Frida Belinky ◽  
Vladimir Pavlenko ◽  
Svetlana A. Shabalina ◽  
David M. Kristensen ◽  
...  

Serine is the only amino acid that is encoded by two disjoint codon sets so that a tandem substitution of two nucleotides is required to switch between the two sets. Previously published evidence suggests that, for the most evolutionarily conserved serines, the codon set switch occurs by simultaneous substitution of two nucleotides. Here we report a genome-wide reconstruction of the evolution of serine codons in triplets of closely related species from diverse prokaryotes and eukaryotes. The results indicate that the great majority of codon set switches proceed by two consecutive nucleotide substitutions, via a threonine or cysteine intermediate, and are driven by selection. These findings imply a strong pressure of purifying selection in protein evolution, which in the case of serine codon set switches occurs via an initial deleterious substitution quickly followed by a second, compensatory substitution. The result is frequent reversal of amino acid replacements and, at short evolutionary distances, pervasive homoplasy.


Blood ◽  
2012 ◽  
Vol 119 (2) ◽  
pp. 388-398 ◽  
Author(s):  
Yongsheng Huang ◽  
Kajal Sitwala ◽  
Joel Bronstein ◽  
Daniel Sanders ◽  
Monisha Dandekar ◽  
...  

The clustered homeobox proteins play crucial roles in development, hematopoiesis, and leukemia, yet the targets they regulate and their mechanisms of action are poorly understood. Here, we identified the binding sites for Hoxa9 and the Hox cofactor Meis1 on a genome-wide level and profiled their associated epigenetic modifications and transcriptional targets. Hoxa9 and the Hox cofactor Meis1 cobind at hundreds of highly evolutionarily conserved sites, most of which are distant from transcription start sites. These sites show high levels of histone H3K4 monomethylation and CBP/P300 binding characteristic of enhancers. Furthermore, a subset of these sites shows enhancer activity in transient transfection assays. Many Hoxa9 and Meis1 binding sites are also bound by PU.1 and other lineage-restricted transcription factors previously implicated in establishment of myeloid enhancers. Conditional Hoxa9 activation is associated with CBP/P300 recruitment, histone acetylation, and transcriptional activation of a network of proto-oncogenes, including Erg, Flt3, Lmo2, Myb, and Sox4. Collectively, this work suggests that Hoxa9 regulates transcription by interacting with enhancers of genes important for hematopoiesis and leukemia.


Cell ◽  
2006 ◽  
Vol 124 (6) ◽  
pp. 1155-1168 ◽  
Author(s):  
Michael Downey ◽  
Rebecca Houlsworth ◽  
Laura Maringele ◽  
Adrienne Rollie ◽  
Marc Brehme ◽  
...  

Cell ◽  
2010 ◽  
Vol 143 (4) ◽  
pp. 628-638 ◽  
Author(s):  
G. Gregory Neely ◽  
Andreas Hess ◽  
Michael Costigan ◽  
Alex C. Keene ◽  
Spyros Goulas ◽  
...  

2006 ◽  
Vol 300 (1) ◽  
pp. 121-131 ◽  
Author(s):  
Jenifer C. Croce ◽  
Shu-Yu Wu ◽  
Christine Byrum ◽  
Ronghui Xu ◽  
Louise Duloquin ◽  
...  

2019 ◽  
Vol 20 (3) ◽  
pp. 775 ◽  
Author(s):  
Zipeng Yu ◽  
Yang Xu ◽  
Lin Liu ◽  
Yarong Guo ◽  
Xisen Yuan ◽  
...  

Background: The C-terminally encoded peptide (CEP) family has been shown to play vital roles in plant growth. Although a genome-wide analysis of this family has been performed in Arabidopsis, little is known regarding CEPs in apple (Malus domestica). Methods: Here, a comprehensive bioinformatics approach was applied to identify MdCEPs in apple, and 12 MdCEP genes were identified and distributed on 6 chromosomes. Results: MdCEP1 peptide had an inhibitory effect on root growth of apple seedlings, indicating that MdCEP1 played a negative role in root development. In addition, the serine and glycine residues remained conserved within the CEP domains, and MdCEP1 lost its function after mutation of these two key amino acids, suggesting that Ser10 and Gly14 residues are crucial for MdCEPs-mediated root growth of apple. Encouragingly, multiple sequence alignment of 273 CEP domains showed that Ser10 residue was evolutionarily conserved in monocot and eudicot plants. MdCEP derivative (Ser to Cys) lost the ability to inhibit the root growth of Nicotiana benthamiana, Setaria italic, Samolous parviflorus, and Raphanus sativus L. and up-regulate the NO3− importer gene NRT2.1. Conclusion: Taken together, Ser10 residue is crucial for CEP function exertion in higher land plants, at least in apple.


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