More Like this

1. Many-to-one binding by intrinsically disordered protein regions

   https://doi.org/10.1142/9789811215636_0015  

   Alterovitz, W L; Faraggi, E; Oldfield, C J; Meng, J W; Xue, B; Huang, F; Romero, P; Kloczkowski, A; Uversky, V N; Dunker, A K. (January 2020, Pacific symposium on biocomputing)

   Disordered binding regions (DBRs), which are embedded within intrinsically disordered proteins or regions (IDPs or IDRs), enable IDPs or IDRs to mediate multiple protein-protein interactions. DBR-protein complexes were collected from the Protein Data Bank for which two or more DBRs having different amino acid sequences bind to the same (100% sequence identical) globular protein partner, a type of interaction herein called many-to-one binding. Two distinct binding profiles were identified: independent and overlapping. For the overlapping binding profiles, the distinct DBRs interact by means of almost identical binding sites (herein called “similar”), or the binding sites contain both common and divergent interaction residues (herein called “intersecting”). Further analysis of the sequence and structural differences among these three groups indicate how IDP flexibility allows different segments to adjust to similar, intersecting, and independent binding pockets. 

   more » « less
2. ParSe 2.0: A web tool to identify drivers of protein phase separation at the proteome level

   https://doi.org/10.1002/pro.4756  

   Wilson, Colorado; Lewis, Karen A.; Fitzkee, Nicholas C.; Hough, Loren E.; Whitten, Steven T. (September 2023, Protein Science)

   Abstract We have developed an algorithm, ParSe, which accurately identifies from the primary sequence those protein regions likely to exhibit physiological phase separation behavior. Originally, ParSe was designed to test the hypothesis that, for flexible proteins, phase separation potential is correlated to hydrodynamic size. While our results were consistent with that idea, we also found that many different descriptors could successfully differentiate between three classes of protein regions: folded, intrinsically disordered, and phase‐separating intrinsically disordered. Consequently, numerous combinations of amino acid property scales can be used to make robust predictions of protein phase separation. Built from that finding, ParSe 2.0 uses an optimal set of property scales to predict domain‐level organization and compute a sequence‐based prediction of phase separation potential. The algorithm is fast enough to scan the whole of the human proteome in minutes on a single computer and is equally or more accurate than other published predictors in identifying proteins and regions within proteins that drive phase separation. Here, we describe a web application for ParSe 2.0 that may be accessed through a browser by visiting https://stevewhitten.github.io/Parse_v2_FASTA to quickly identify phase‐separating proteins within large sequence sets, or by visiting https://stevewhitten.github.io/Parse_v2_web to evaluate individual protein sequences. 

   more » « less
3. Intramolecular interactions between folded and disordered regions shape ubiquilin structure and function

   https://doi.org/10.64898/2026.03.13.711692  

   Niblo, Jessica K; Acharya, Nirbhik; Watkins, Maxwell B; Castañeda, Carlos A; Sukenik, Shahar (March 2026, bioRxiv)

   Abstract Multidomain proteins consist of folded domains connected by intrinsically disordered regions. The flexibility afforded by the disordered regions coupled to the structure and surface chemistry of folded regions allows for unique structural and functional features in these proteins. Yet how intramolecular interactions between disordered regions and folded domains affect multidomain protein structure and function remain poorly understood. Here we use a range of biophysical and computational approaches to measure the intramolecular interactions between the folded domains and disordered regions of ubiquilins (UBQLNs) - essential components of protein quality control that shuttle poly-ubiquitinated client proteins to proteasomal degradation or autophagy. Starting with the yeast UBQLN homolog Dsk2, we find that interactions between two folded domains located at the opposite ends of UBQLN bring about a closed conformation. The prevalence of this closed conformation, however, is modulated by intramolecular interactions involving the disordered regions and folded STI1 domain at the center of the protein. Simulations and analysis of UBQLN homologs across multiple eukaryotic lineages reveals that these disordered:folded domain interactions exist in some UBQLN homologs but are absent in others, indicating possible fundamental differences in function among proteins with the same multidomain architecture. 

   more » « less
4. Intra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding

   https://doi.org/10.1038/s41467-023-43098-1  

   Qiu, Chen; Zhang, Zihan; Wine, Robert N; Campbell, Zachary T; Zhang, Jun; Hall, Traci_M Tanaka (December 2023, Nature Communications)

   Abstract PUF proteins are characterized by globular RNA-binding domains. They also interact with partner proteins that modulate their RNA-binding activities.Caenorhabditis elegansPUF proteinfem-3binding factor-2 (FBF-2) partners with intrinsically disordered Lateral Signaling Target-1 (LST-1) to regulate target mRNAs in germline stem cells. Here, we report that an intrinsically disordered region (IDR) at the C-terminus of FBF-2 autoinhibits its RNA-binding affinity by increasing the off rate for RNA binding. Moreover, the FBF-2 C-terminal region interacts with its globular RNA-binding domain at the same site where LST-1 binds. This intramolecular interaction restrains an electronegative cluster of amino acid residues near the 5′ end of the bound RNA to inhibit RNA binding. LST-1 binding in place of the FBF-2 C-terminus therefore releases autoinhibition and increases RNA-binding affinity. This regulatory mechanism, driven by IDRs, provides a biochemical and biophysical explanation for the interdependence of FBF-2 and LST-1 in germline stem cell self-renewal. 

   more » « less
5. Empirical Assessment of Sequence-Based Predictions of Intrinsically Disordered Regions Involved in Phase Separation

   https://doi.org/10.3390/biom15081079  

   Wu, Xuantai; Wang, Kui; Hu, Gang; Kurgan, Lukasz (August 2025, Biomolecules)

   Phase separation processes facilitate the formation of membrane-less organelles and involve interactions within structured domains and intrinsically disordered regions (IDRs) in protein sequences. The literature suggests that the involvement of proteins in phase separation can be predicted from their sequences, leading to the development of over 30 computational predictors. We focused on intrinsic disorder due to its fundamental role in related diseases, and because recent analysis has shown that phase separation can be accurately predicted for structured proteins. We evaluated eight representative amino acid-level predictors of phase separation, capable of identifying phase-separating IDRs, using a well-annotated, low-similarity test dataset under two complementary evaluation scenarios. Several methods generate accurate predictions in the easier scenario that includes both structured and disordered sequences. However, we demonstrate that modern disorder predictors perform equally well in this scenario by effectively differentiating phase-separating IDRs from structured regions. In the second, more challenging scenario—considering only predictions in disordered regions—disorder predictors underperform, and most phase separation predictors produce only modestly accurate results. Moreover, some predictors are broadly biased to classify disordered residues as phase-separating, which results in low predictive performance in this scenario. Finally, we recommend PSPHunter as the most accurate tool for identifying phase-separating IDRs in both scenarios. 

   more » « less