scholarly journals Co-translational assembly counteracts promiscuous interactions

2021 ◽  
Author(s):  
Maximilian Seidel ◽  
Anja Becker ◽  
Filipa Pereira ◽  
Jonathan J.M. Landry ◽  
Nayara Trevisan Doimo de Azevedo ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Coiled Coils ◽  
Ribosome Profiling ◽  
Structural Motifs ◽  
Short Linear Motifs ◽  
Physiological Relevance ◽  
Nascent Chain ◽  
Regulatory Complexity ◽  
Linear Motifs ◽  
Assembly Pathways

During the co-translational assembly of protein complexes, a fully synthesized subunit engages with the nascent chain of a newly synthesized interaction partner. Such events are thought to contribute to productive assembly, but their exact physiological relevance remains underexplored. Here, we examined structural motifs contained in nucleoporins for their potential to facilitate co-translational assembly. We experimentally tested candidate structural motifs and identified several previously unknown co-translational interactions. We demonstrate by selective ribosome profiling that domain invasion motifs of beta-propellers, coiled-coils, and short linear motifs act as co-translational assembly domains. Such motifs are often contained in proteins that are members of multiple complexes (moonlighters) and engage with closely related paralogs. Surprisingly, moonlighters and paralogs assembled co-translationally in only one but not all of the relevant assembly pathways. Our results highlight the regulatory complexity of assembly pathways.

scholarly journals Interface size drives cotranslational assembly of protein complexes

2021 ◽  
Author(s):  
Mihaly Badonyi ◽  
Joseph A Marsh
Keyword(s):  
Structure Data ◽  
Protein Complexes ◽  
Ribosome Profiling ◽  
Specific Structure ◽  
Complex Assembly ◽  
Nascent Chain ◽  
Assembly Pathways ◽  
Biological Context

Assembly pathways of protein complexes should be precise and efficient to minimise misfolding and unwanted interactions with other proteins in the cell. One way to achieve this is by seeding complex assembly during translation via nascent chain engagement. Here, we considered the possibility that the propensity of subunits to cotranslationally assemble is ingrained within the interface hierarchy of protein complexes. Using a combination of proteome-specific structure data and assembly-onset positions determined by ribosome profiling, we show that larger interfaces are prioritised in the course of cotranslational assembly. We observe that this effect is not exclusive to homomeric complexes, but appears to drive the assembly of heteromeric subunits, to the extent that interface size differences are detectable between N and C-terminal locations, with the former being larger on average. We provide explanations to this phenomenon and discuss its importance in a biological context.

scholarly journals Computational Investigation Of Structural Interfaces Of Protein Complexes With Short Linear Motifs

2020 ◽  
Author(s):  
Raghavender Surya Upadhyayula
Keyword(s):  
Protein Complexes ◽  
Geometric Features ◽  
Computational Investigation ◽  
Contact Residue ◽  
Short Linear Motifs ◽  
Peptide Complexes ◽  
Linear Motifs ◽  
Regulatory Functions ◽  
Structural Interfaces ◽  
Interface Residues

AbstractProtein complexes with short linear motifs (SLiMs) are known to play important regulatory functions in eukaryotes. In this investigation, I have studied the structures deposited in PDB with SLiMs. The structures Were grouped into three broad categories of protein-protein, protein-peptide and the rest as others. Protein-peptide complexes Were found to be most highly represented. The interfaces Were evaluated for geometric features and conformational variables. It was observed that protein-protein and protein-peptide complexes show characteristic differences in residue pairings, which Were quantified by evaluating normalized contact residue pairing frequencies. Interface residues adopt characteristic canonical residue conformations in the Ramachandran space, with a pronounced preference for positive ϕ conformations. It was observed that phosphorylated residues have an unusual propensity to adopt the unusual positive ϕ conformations at the interface.

scholarly journals Short Linear Motifs Characterizing Snake Venom and Mammalian Phospholipases A2

Toxins ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 290
Author(s):  
Caterina Peggion ◽  
Fiorella Tonello
Keyword(s):  
Snake Venom ◽  
Protein Interactions ◽  
Biological Properties ◽  
Protein Protein Interactions ◽  
Sequence Alignments ◽  
Toxic Activity ◽  
Short Linear Motifs ◽  
Phospholipases A2 ◽  
Group I ◽  
Linear Motifs

Snake venom phospholipases A2 (PLA2s) have sequences and structures very similar to those of mammalian group I and II secretory PLA2s, but they possess many toxic properties, ranging from the inhibition of coagulation to the blockage of nerve transmission, and the induction of muscle necrosis. The biological properties of these proteins are not only due to their enzymatic activity, but also to protein–protein interactions which are still unidentified. Here, we compare sequence alignments of snake venom and mammalian PLA2s, grouped according to their structure and biological activity, looking for differences that can justify their different behavior. This bioinformatics analysis has evidenced three distinct regions, two central and one C-terminal, having amino acid compositions that distinguish the different categories of PLA2s. In these regions, we identified short linear motifs (SLiMs), peptide modules involved in protein–protein interactions, conserved in mammalian and not in snake venom PLA2s, or vice versa. The different content in the SLiMs of snake venom with respect to mammalian PLA2s may result in the formation of protein membrane complexes having a toxic activity, or in the formation of complexes whose activity cannot be blocked due to the lack of switches in the toxic PLA2s, as the motif recognized by the prolyl isomerase Pin1.

scholarly journals Resources to Discover and Use Short Linear Motifs in Viral Proteins

2020 ◽  
Vol 38 (1) ◽  
pp. 113-127 ◽  
Author(s):  
Peter Hraber ◽  
Paul E. O’Maille ◽  
Andrew Silberfarb ◽  
Katie Davis-Anderson ◽  
Nicholas Generous ◽  
...  
Keyword(s):  
Viral Proteins ◽  
Short Linear Motifs ◽  
Linear Motifs

scholarly journals Inhibitory activities of short linear motifs underlie Hox interactome specificity in vivo

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Manon Baëza ◽  
Séverine Viala ◽  
Marjorie Heim ◽  
Amélie Dard ◽  
Bruno Hudry ◽  
...  
Keyword(s):  
Cell Fate ◽  
Drosophila Embryo ◽  
Traditional Role ◽  
Hox Proteins ◽  
Short Linear Motifs ◽  
Wide Range ◽  
Mouse Species ◽  
Inhibitory Activities ◽  
Linear Motifs

Hox proteins are well-established developmental regulators that coordinate cell fate and morphogenesis throughout embryogenesis. In contrast, our knowledge of their specific molecular modes of action is limited to the interaction with few cofactors. Here, we show that Hox proteins are able to interact with a wide range of transcription factors in the live Drosophila embryo. In this context, specificity relies on a versatile usage of conserved short linear motifs (SLiMs), which, surprisingly, often restrains the interaction potential of Hox proteins. This novel buffering activity of SLiMs was observed in different tissues and found in Hox proteins from cnidarian to mouse species. Although these interactions remain to be analysed in the context of endogenous Hox regulatory activities, our observations challenge the traditional role assigned to SLiMs and provide an alternative concept to explain how Hox interactome specificity could be achieved during the embryonic development.

scholarly journals A comprehensive motifs-based interactome of the C/EBPα transcription factor

2020 ◽  
Author(s):  
Evelyn Ramberger ◽  
Valeria Sapozhnikova ◽  
Elisabeth Kowenz-Leutz ◽  
Karin Zimmermann ◽  
Nathalie Nicot ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Protein Interaction ◽  
Intrinsically Disordered Proteins ◽  
Arginine Methylation ◽  
Disordered Proteins ◽  
List Type ◽  
Short Linear Motifs ◽  
Intrinsically Disordered ◽  
Linear Motifs ◽  
Factor C

AbstractThe pioneering transcription factor C/EBPα coordinates cell fate and cell differentiation. C/EBPα represents an intrinsically disordered protein with multiple short linear motifs and extensive post-translational side chain modifications (PTM), reflecting its modularity and functional plasticity. Here, we combined arrayed peptide matrix screening (PRISMA) with biotin ligase proximity labeling proteomics (BioID) to generate a linear, isoform specific and PTM-dependent protein interaction map of C/EBPα in myeloid cells. The C/EBPα interactome comprises promiscuous and PTM-regulated interactions with protein machineries involved in gene expression, epigenetics, genome organization, DNA replication, RNA processing, and nuclear transport as the basis of functional C/EBPα plasticity. Protein interaction hotspots were identified that coincide with homologous conserved regions of the C/EBP family and revealed interaction motifs that score as molecular recognition features (MoRF). PTMs alter the interaction spectrum of multi-valent C/EBP-motifs to configure a multimodal transcription factor hub that allows interaction with multiple co-regulatory components, including BAF/SWI-SNF or Mediator complexes. Combining PRISMA and BioID acts as a powerful strategy to systematically explore the interactomes of intrinsically disordered proteins and their PTM-regulated, multimodal capacity.Key pointsIntegration of proximity labeling and arrayed peptide screen proteomics refines the interactome of C/EBPα isoformsHotspots of protein interactions in C/EBPα mostly occur in conserved short linear motifsInteractions of the BAF/SWI-SNF complex with C/EBPα are modulated by arginine methylation and isoform statusThe integrated experimental strategy suits systematic interactome studies of intrinsically disordered proteins

scholarly journals Ribosome elongation kinetics of consecutively charged residues are coupled to electrostatic force

2021 ◽  
Author(s):  
Sarah E Leininger ◽  
Judith Rodriguez ◽  
Quyen V Vu ◽  
Yang Jiang ◽  
Ma Suan Li ◽  
...  
Keyword(s):  
Amino Acid ◽  
Conformational Changes ◽  
Electrostatic Force ◽  
Ribosome Profiling ◽  
Peptide Bond Formation ◽  
Translation Speed ◽  
Charged Residues ◽  
Nascent Chain ◽  
Chain Conformations

The speed of protein synthesis can dramatically change when consecutively charged residues are incorporated into an elongating nascent protein by the ribosome. The molecular origins of this class of allosteric coupling remain unknown. We demonstrate, using multi-scale simulations, that positively charged residues generate large forces that pull the P-site amino acid away from the A-site amino acid. Negatively charged residues generate forces of similar magnitude but opposite direction. And that these conformational changes, respectively, raise and lower the transition state barrier height to peptide bond formation, explaining how charged residues mechanochemically alter translation speed. This mechanochemical mechanism is consistent with in vivo ribosome profiling data exhibiting a proportionality between translation speed and the number of charged residues, experimental data characterizing nascent chain conformations, and a previously published cryo-EM structure of a ribosome-nascent chain complex containing consecutive lysines. These results expand the role of mechanochemistry in translation, and provide a framework for interpreting experimental results on translation speed.

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