**2. Review**

Sánchez-López et al. report about the structural determinants of the N-terminus of the prion protein and the effect of binding copper ions in their review. They discuss the current knowledge of how mutations can impact the copper-binding properties of prion protein both in health and disease progression [36].

In their review paper Ciemny et al. first introduced the technique of Monte Carlo and other simulation for predicting possible structures of unstructured protein, protein-peptide complexes and unfolded states of globular proteins. They presented several case studies on various disordered proteins. They also proposed the use of the CABS coarse-grained model with Monte Carlo sampling scheme. They also show that CABS can be combined with the use of experimental data too [37].

The literature information on the alteration of disordered proteins in neurodegenerative and other diseases reported in this review. Martinelli et al. discussed how the misfolded proteins can be involved in Alzheimer's, Parkinson's and other diseases. The most common form of misfolding IDPs is the formation of neurotoxic amyloid plaques. The review discusses important special cases of beta-amyloid, alpha-synuclein, tau etc. They also show drug candidates for later use in to treatment of diseases caused by misfolded IDPs [38].

This is the first review from the Greb-Markiewicz lab in which Kolonko and Greb-Markiewicz summarized our current knowledge on helix-loop-helix/Per-ARNT-SIM (bHLH–PAS) proteins, considering their structures and intrinsic disorder nature based on NMR and X-ray analysis. Currently, all determined structures comprise only selected domains (bHLH and/or PAS), while parts of proteins, comprising their long C-termini, have not been structurally characterized yet since these regions appear to be intrinsically disordered. These intrinsically disordered parts contribute a lot to the flexibility and function of these proteins [39].

The second review from the same lab is the paper of Tarczewska and Greb-Markiewicz which is a follow-up publication of the review paper of Kolonko and Greb-Markiewicz [39], the currently available information on "The Significance of the Intrinsically Disordered Regions for the Function of the BHLH Transcription Factors" is reported. Their aim was to emphasize the significance of existing disordered regions within the helix–loop–helix (bHLH) transcription factors for their functionality [40].

Finally, in the last review paper of this collection, Owen and Shewmaker summarized our current knowledge on "The Role of Post-Translational Modification in the Phase Transition of Intrinsically Disordered Proteins". They pointed that intrinsically disordered regions are critical to the liquid–liquid phase separation that facilitates specialized cellular functions and discuss how post-translational modifications of intrinsically disordered protein segments can regulate the molecular condensation of macromolecules into functional phase-separated complexes [41].

### **3. Concept**

In his concept paper, Rikkerin, E.H.A. considers the "first line response" role of disordered protein in the protection against pathogens and disease. He presents several examples of how disorder and post-translational changes can play in the response of organisms to the stress of a changing environment. He proposes that some disordered proteins enable organisms to sense and react rapidly as the first line responds [42].

**Funding:** Hungarian Research and Developments Fund OTKA K115698.

**Conflicts of Interest:** The author declares no conflict of interest.
