Our notions of protein function have long been determined by the protein structure–function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed ‘random fuzziness’. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation.
cyclophilin D (cypD) is a peptidyl-prolyl isomerase expressed in the nucleus and transported into the mitochondria where it is best associated with the regulation of the mitochondrial permeability transition pore (Mptp). there are, however, other possible roles of cypD in the mitochondria which may or may not be linked with the Mptp. Alpha synuclein (αSyn) is shown here to interact directly with cypD via its acidic proline-rich c-terminus region and binding at the putative ligand binding pocket of cypD. the study shows that cypD binding with soluble αSyn prevents its aggregation. furthermore, the addition of cypD to preformed αSyn fibrils leads to the disassembly of these fibrils. Enzymaticallycompromised mutants of cypD show reduced abilities to dissociate αSyn aggregates, suggesting that fibril disassembly is linked to the increased rate of peptidyl-prolyl isomerisation catalysed by CypD. protein aggregation in the mitochondria is increasingly seen as the cause of neurodegeneration. However, protein aggregation is a reversible process but disaggregation requires help from other proteins such as isomerases and chaperones. the results here demonstrate a possible mechanism by which cypD achieves this and suggest that disaggregation could be one of the many functions of this protein. Cyclophilin D (CypD) is a mitochondrial peptidyl-prolyl isomerase that has been implicated to be involved in the mechanisms of many diseases, although it is best known as a regulator for the opening of the mitochondria permeability transition pore (MPTP). These conclusions were drawn from outcomes observed in in vivo studies involving the use of the potent inhibitor, cyclosporine A (CsA), and ppif gene knockdown mice 1,2. In a recent study, genetic ablation of CypD resulted in a delayed onset of Parkinson's Disease (PD) and extended lifespan of PD mice 3. Co-immunoprecipitation experiments in the same study show very weak direct interactions between CypD and αSyn 3. The connection between CypD and PD has not been clearly established, with the exception that mitochondrial dysfunction is a hallmark of PD 4. PD is characterised by the formation of Lewy bodies, which are protein aggregates containing the protein alpha-synuclein (αSyn) and selective degeneration of dopaminergic neurons in the substantia nigra brain region 5,6. Genome-wide analyses place mutations in SNCA, the gene encoding αSyn, as the top risk factor for those developing sporadic forms of the disease 7,8. αSyn redistributes from the cytoplasm to the outer and inner mitochondrial membrane with increased accumulation in PD 9,10. There is a correlation between αSyn entry into the mitochondria, reduced mitochondrial membrane potential (∆Ψ m) and mitochondria dysfunction, implicating the involvement of the MPTP 11,12. These effects of αSyn can be rescued by the addition of CsA, a CypD inhibitor, although this could be through the role of CypD as a regulator of the MPTP rather than as a result of direct interaction between αSyn and CypD 13. Proteins currently known to dissociate...
α-Synuclein (aSyn) aggregation is an attractive target for therapeutic development for a range of neurodegenerative conditions, collectively termed synucleinopathies. Here, we probe the mechanism of action of a peptide 4554W, (KDGIVNGVKA), previously identified through intracellular library screening, to prevent aSyn aggregation and associated toxicity. We utilize NMR to probe association and identify that 4554W associates with a “partially aggregated” form of aSyn, with enhanced association occurring over time. We also report the ability of 4554W to undergo modification through deamidation of the central asparagine residue, occurring on the same timescale as aSyn aggregation in vitro , with peptide modification enhancing its association with aSyn. Additionally, we report that 4554W can act to reduce fibril formation of five Parkinson’s disease associated aSyn mutants. Inhibitory peptide binding to partially aggregated forms of aSyn, as identified here, is particularly attractive from a therapeutic perspective, as it would eliminate the need to administer the therapy at pre-aggregation stages, which are difficult to diagnose. Taken together the data suggest that 4554W could be a suitable candidate for future therapeutic development against wild-type, and most mutant aSyn aggregation.
Bacteria use an array of sigma factors to regulate gene expression during different stages of their life cycles. Full-length, atomic-level structures of sigma factors have been challenging to obtain experimentally as a result of their many regions of intrinsic disorder. AlphaFold has now supplied plausible full-length models for most sigma factors. Here we discuss the current understanding of the structures and functions of sigma factors in the model organism, Bacillus subtilis, and present an X-ray crystal structure of a region of B. subtilis SigE, a sigma factor that plays a critical role in the developmental process of spore formation.
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