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Precise control of protein and messenger RNA (mRNA) degradation is essential for cellular metabolism and homeostasis. Controlled and specific degradation of both molecular species necessitates their engagements with the respective degradation machineries; this engagement involves a disordered/unstructured segment of the substrate traversing the degradation tunnel of the machinery and accessing the catalytic sites. However, while molecular factors influencing protein degradation have been extensively explored on a genome scale, and in multiple organisms, such a comprehensive understanding remains missing for mRNAs. Here, we analyzed multiple genome‐scale experimental yeast mRNA half‐life data in light of experimentally derived mRNA secondary structures and protein binding data, along with high‐resolution X‐ray crystallographic structures of the RNase machines. Results unraveled a consistent genome‐scale trend that mRNAs comprising longer terminal and/or internal unstructured segments have significantly shorter half‐lives; the lengths of the 5′‐terminal, 3′‐terminal, and internal unstructured segments that affect mRNA half‐life are compatible with molecular structures of the 5′ exo‐, 3′ exo‐, and endoribonuclease machineries. Sequestration into ribonucleoprotein complexes elongates mRNA half‐life, presumably by burying ribonuclease engagement sites under oligomeric interfaces. After gene duplication, differences in terminal unstructured lengths, proportions of internal unstructured segments, and oligomerization modes result in significantly altered half‐lives of paralogous mRNAs. Side‐by‐side comparison of molecular principles underlying controlled protein and mRNA degradation in yeast unravels their remarkable mechanistic similarities and suggests how the intrinsic structural features of the two molecular species, at two different levels of the central dogma, regulate their half‐lives on genome scale. [ABSTRACT FROM AUTHOR]

Interactions between distantly placed amino acids in the primary chain (long-range) play a very crucial role in the formation and stabilization of the tertiary structure of a protein, while interactions between closely placed amino acids in the primary chain (short-range) mostly stabilize the secondary structures. Every protein needs to maintain marginal stability in order to perform its physiological functions in its native environment. The requirements for this stability in mesophilic and thermophilic proteins are different. Thermophilic proteins need to form more interactions as well as more stable interactions to survive in the extreme environment, they live in. Here, we aim to find out how the interacting amino acids in three-dimensional space are positioned in the primary chains in thermophilic and mesophilic. How does this arrangement help thermophiles to maintain their structural integrity at high temperatures? Working on a dataset of 1560 orthologous pairs we perceive that thermophiles are not only enriched with long-range interactions, they feature bigger connected clusters and higher network densities compared to their mesophilic orthologs, at higher interaction strengths between the amino acids. Moreover, we have observed the enrichment of different types of interactions at different secondary structural regions. [Display omitted] • Protein contact network helps in understanding thermal stability. • Diverse thermo-meso orthologs reveal distinguishable differences in network properties. • Thermophilic Van der Waals LRNs feature larger connected components. • Thermophilic proteins exhibit denser Van der Waals LRNs. • Coulombic SRNs display higher attractive ̶ repulsive interactions in thermophilic. [ABSTRACT FROM AUTHOR]

Numerous biological proteins exhibit intrinsic disorder at their termini, which are associated with multifarious functional roles. Here, we show the surprising result that an increased percentage of terminal short transiently disordered regions with enhanced flexibility (Tst DREF) is associated with accelerated folding rates of globular proteins. Evolutionary conservation of predicted disorder at Tst DREFs and drastic alteration of folding rates upon point-mutations suggest critical regulatory role(s) of Tst DREFs in shaping the folding kinetics. Tst DREFs are associated with long-range intramolecular interactions and the percentage of native secondary structural elements physically contacted by Tst DREFs exhibit another surprising positive correlation with folding kinetics. These results allow us to infer probable molecular mechanisms behind the Tst DREF-mediated regulation of folding kinetics that challenge protein biochemists to assess by direct experimental testing. [ABSTRACT FROM AUTHOR]

Folding rates (ln k f ) of globular proteins correlate with their biophysical properties, but relationship between ln k f and patterns of sequence evolution remains elusive. We introduce ‘relative co-evolution order’ ( rCEO ) as length-normalized average primary chain separation of co-evolving pairs (CEPs), which negatively correlates with ln k f . In addition to pairs in native 3D contact, indirectly connected and structurally remote CEPs probably also play critical roles in protein folding. Correlation between rCEO and ln k f is stronger in multi-state proteins than two-state proteins, contrasting the case of contact order ( co ), where stronger correlation is found in two-state proteins. Finally, rCEO , co and ln k f are fitted into a 3D linear correlation. [ABSTRACT FROM AUTHOR]

Here we compare the structural and evolutionary attributes of Thermus thermophilus and Escherichia coli small ribosomal subunits (SSU). Our results indicate that with few exceptions, thermophilic 16S ribosomal RNA (16S rRNA) is densely packed compared to that of mesophilic at most of the analogous spatial regions. In addition, we have located species-specific cavity clusters (SSCCs) in both species. E. coli SSCCs are numerous and larger compared to T. thermophilus SSCCs, which again indicates densely packed thermophilic 16S rRNA. Thermophilic ribosomal proteins (r-proteins) have longer disordered regions than their mesophilic homologs and they experience larger disorder-to-order transitions during SSU-assembly. This is reflected in the predicted higher conformational changes of thermophilic r-proteins compared to their mesophilic homologs during SSU-assembly. This high conformational change of thermophilic r-proteins may help them to associate with the 16S ribosomal RNA with high complementary interfaces, larger interface areas, and denser molecular contacts, compared to those of mesophilic. Thus, thermophilic protein-rRNA interfaces are tightly associated with 16S rRNA than their mesophilic homologs. Densely packed 16S rRNA interior and tight protein-rRNA binding of T. thermophilus (compared to those of E. coli) are likely the signatures of its thermal adaptation. We have found a linear correlation between the free energy of protein-RNA interface formation, interface size, and square of conformational changes, which is followed in both prokaryotic and eukaryotic SSU. Disorder is associated with high protein-RNA interface polarity. We have found an evolutionary tendency to maintain high polarity (thereby disorder) at protein-rRNA interfaces, than that at rest of the protein structures. However, some proteins exhibit exceptions to this general trend. [ABSTRACT FROM AUTHOR]

Background: The three-dimensional structure of a protein can be described as a graph where nodes represent residues and the strength of non-covalent interactions between them are edges. These protein contact networks can be separated into long and short-range interactions networks depending on the positions of amino acids in primary structure. Long-range interactions play a distinct role in determining the tertiary structure of a protein while short-range interactions could largely contribute to the secondary structure formations. In addition, physico chemical properties and the linear arrangement of amino acids of the primary structure of a protein determines its three dimensional structure. Here, we present an extensive analysis of protein contact subnetworks based on the London van der Waals interactions of amino acids at different length scales. We further subdivided those networks in hydrophobic, hydrophilic and charged residues networks and have tried to correlate their influence in the overall topology and organization of a protein. Results: The largest connected component (LCC) of long (LRN)-, short (SRN)- and all-range (ARN) networks within proteins exhibit a transition behaviour when plotted against different interaction strengths of edges among amino acid nodes. While short-range networks having chain like structures exhibit highly cooperative transition; long- and all-range networks, which are more similar to each other, have non-chain like structures and show less cooperativity. Further, the hydrophobic residues subnetworks in long- and all-range networks have similar transition behaviours with all residues all-range networks, but the hydrophilic and charged residues networks don't. While the nature of transitions of LCC's sizes is same in SRNs for thermophiles and mesophiles, there exists a clear difference in LRNs. The presence of larger size of interconnected long-range interactions in thermophiles than mesophiles, even at higher interaction strength between amino acids, give extra stability to the tertiary structure of the thermophiles. All the subnetworks at different length scales (ARNs, LRNs and SRNs) show assortativity mixing property of their participating amino acids. While there exists a significant higher percentage of hydrophobic subclusters over others in ARNs and LRNs; we do not find the assortative mixing behaviour of any the subclusters in SRNs. The clustering coefficient of hydrophobic subclusters in long-range network is the highest among types of subnetworks. There exist highly cliquish hydrophobic nodes followed by charged nodes in LRNs and ARNs; on the other hand, we observe the highest dominance of charged residues cliques in short-range networks. Studies on the perimeter of the cliques also show higher occurrences of hydrophobic and charged residues' cliques. Conclusions: The simple framework of protein contact networks and their subnetworks based on London van der Waals force is able to capture several known properties of protein structure as well as can unravel several new features. The thermophiles do not only have the higher number of long-range interactions; they also have larger cluster of connected residues at higher interaction strengths among amino acids, than their mesophilic counterparts. It can reestablish the significant role of long-range hydrophobic clusters in protein folding and stabilization; at the same [ABSTRACT FROM AUTHOR]

A compensatory mutation (CM) counter balances lethal effects of a deleterious mutation (DM), ensuring the persistence of both through natural selection. However, little is known about the biological aspects of CMs those restore the structural alterations of proteins caused by slightly DMs. Here, by analyzing the evolution of the UDP-glycosyltransferase 73B4 protein among monocot-dicot plants, we investigate the occurrence of CMs around slightly DMs in 3D space. Our results illustrate that CMs exhibit significantly higher tendency to occur within the range of electrostatic interaction around the slightly DMs, compared to occurring randomly in the protein. [ABSTRACT FROM AUTHOR]