Protein folding and quinary interactions: creating cellular organisation through functional disorder

Ribeiro, Sara S.; Ebbinghaus, Simon; Marcos, João Carlos

doi:10.1002/1873-3468.13211

Cited by 23 publications

(13 citation statements)

References 159 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nuclear dynamics, among other crucial cellular processes, has been recently established to be tuned, at least in part, by the widespread phenomenon of phase separation [1]. After a decade of active research, it is now accepted that this demixing process is a thermodynamicallydriven phenomenon, giving rise to a variety of dynamic bodies (i.e., biomolecular condensates, BMCs), primarily composed of nucleic acids and proteins [2] interacting through quinary interactions [3], frequently involving unstructured portions of proteins, especially intrinsically disordered regions (IDRs) [4,5]. These components are thought to be under the control of effective regulatory systems, through the action of a number of cellular factors which precisely tune the assembly and the de-aggregation of these bodies via post-translational modifications (PTMs), thus promoting a localized induction of condensates [6].…”

Section: Phase Separation In Nuclear Organization and Functions Relatmentioning

confidence: 99%

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Antoniali

Dalla

et al. 2020

Biomolecular Concepts

View full text Add to dashboard Cite

Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are not mandatory for modulating this process. Recent insights about phase-separation mechanisms pointed to new fascinating models that could explain how cells could cope with DNA damage responses, conferring both spatial and temporal fine regulation. APE1 is a multifunctional protein belonging to the Base Excision Repair (BER) pathway, bearing additional ‘non-canonical’ DNA-repair functions associated with processes like RNA metabolism. Recently, it has been highlighted that several DNA repair enzymes, such as 53BP1 and APE1, are endowed with RNA binding abilities. In this work, after reviewing the recent literature supporting a role of LLPS in DDR, we analyze, as a proof of principle, the interactome of APE1 using a bioinformatics approach to look for clues of LLPS in BER. Some of the APE1 interactors are associated with cellular processes in which LLPS has been either proved or proposed and are involved in different pathogenic events. This work might represent a paradigmatical pipeline for evaluating the relevance of LLPS in DDR.

show abstract

Section: Phase Separation In Nuclear Organization and Functions Relatmentioning

confidence: 99%

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Antoniali

Dalla

et al. 2020

Biomolecular Concepts

View full text Add to dashboard Cite

show abstract

“…Evolution of protein function is not just a matter of achieving suitable topology, but also more elusively about tuning the structural properties. The latter involves maintaining sufficient structural stability (58), balancing affinity and interaction promiscuity (59), tuning the quinary interplay, proteome self-organization, intracellular search (60,61), and optimizing the dynamic motions (62)(63)(64). Our present focus is on the evolutionary role of the motions and properties of entire βand α-elements, which has, so far, gained relatively sparse attention (2,65,66).…”

Section: Discussionmentioning

confidence: 99%

Exposing the distinctive modular behavior of β-strands and α-helices in folded proteins

Wang

Logan

Danielsson

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Although folded proteins are commonly depicted as simplistic combinations of β-strands and α-helices, the actual properties and functions of these secondary-structure elements in their native contexts are just partly understood. The principal reason is that the behavior of individual β- and α-elements is obscured by the global folding cooperativity. In this study, we have circumvented this problem by designing frustrated variants of the mixed α/β-protein S6, which allow the structural behavior of individual β-strands and α-helices to be targeted selectively by stopped-flow kinetics, X-ray crystallography, and solution-state NMR. Essentially, our approach is based on provoking intramolecular "domain swap." The results show that the α- and β-elements have quite different characteristics: The swaps of β-strands proceed via global unfolding, whereas the α-helices are free to swap locally in the native basin. Moreover, the α-helices tend to hybridize and to promote protein association by gliding over to neighboring molecules. This difference in structural behavior follows directly from hydrogen-bonding restrictions and suggests that the protein secondary structure defines not only tertiary geometry, but also maintains control in function and structural evolution. Finally, our alternative approach to protein folding and native-state dynamics presents a generally applicable strategy for in silico design of protein models that are computationally testable in the microsecond–millisecond regime.

show abstract

“…Nowadays quinary interactions have sometimes been used to denote nonspecific interactions between proteins and crowders. 7,[30][31][32][33][34][35] We should recall that McConkey's motivation was to explain apparently slower than expected (based on sequence comparison of small soluble proteins) evolution of cellular proteins.…”

Section: Discussionmentioning

confidence: 99%

Both Ligands and Macromolecular Crowders Preferentially Bind to Closed Conformations of Maltose Binding Protein

et al. 2019

View full text Add to dashboard Cite

In cellular environments, proteins not only interact with their specific partners but also encounter a high concentration of bystander macromolecules, or crowders. Nonspecific interactions with macromolecular crowders modulate the activities of proteins, but our knowledge about the rules of nonspecific interactions is still very limited. In previous work, we presented experimental evidence that macromolecular crowders acted competitively in inhibiting the binding of maltose binding protein (MBP) with its ligand maltose. Competition between a ligand and an inhibitor may result from binding to either the same site or different conformations of the protein. Maltose binds to the cleft between two lobes of MBP and, in a series of mutants, the affinities increased with increasing extent of lobe closure. Here we investigated whether macromolecular crowders also have a conformational or site preference when binding to MBP. The affinities of a polymer crowder, Ficoll70, measured by monitoring tryptophan fluorescence were 3-to 6-fold higher for closure mutants than for wild-type MBP. Competition between the ligand and crowder, as indicated by fitting of titration data and directly by NMR spectroscopy, and their similar preferences for closed MBP conformations further suggest the scenario that the crowder, like maltose, preferentially binds to the inter-lobe cleft of MBP. Similar observations were obtained for bovine serum albumin as a protein crowder. Conformational and site preferences in MBP-crowder binding allude to the paradigm that nonspecific interactions can possess hallmarks of molecular recognition, which may be essential for intracellular organizations including colocalization of proteins and liquid-liquid phase separation.

show abstract

Protein folding and quinary interactions: creating cellular organisation through functional disorder

Cited by 23 publications

References 159 publications

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Exposing the distinctive modular behavior of β-strands and α-helices in folded proteins

Both Ligands and Macromolecular Crowders Preferentially Bind to Closed Conformations of Maltose Binding Protein

Contact Info

Product

Resources

About