TYPE Editorial PUBLISHED 14 December 2022 DOI 10.3389/fmolb.2022.1107686 Editorial: Molecular determinants OPEN ACCESS of protein assemblies in health EDITED AND REVIEWED BY Andrea Mozzarelli, University of Parma, Italy and disease *CORRESPONDENCE Sonja Kroschwald, Sonja Kroschwald 1*, Anoop Arunagiri 2*, Salvador Ventura 3*, sonja.kroschwald@bc.biol.ethz.ch Anoop Arunagiri, Srivastav Ranganathan 4* and Verena Kohler 5* anooparu@umich.edu 1 Institut für Biochemie, ETH Zurich, Zurich, Switzerland, 2Department of Internal Medicine, University Salvador Ventura, of Michigan, Ann Arbor, MI, United States, 3Institut de Biotecnologia i Biomedicina and Departament de salvador.ventura@uab.cat Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain, Srivastav Ranganathan, 4 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States, aditya.sia@gmail.com 5 Institute of Molecular Biosciences, University of Graz, Graz, Styria, Austria Verena Kohler, verena.kohler@uni-graz.at SPECIALTY SECTION KEYWORDS This article was submitted to Protein protein structure-function relationship, protein aggregation, amyloid, biomolecular Biochemistry for Basic and Applied condensates, molecular chaperone, neurodegenerative diseasaes, gut microbiome, Sciences, a section of the journal bacterial amyloid Frontiers in Molecular Biosciences RECEIVED 25 November 2022 ACCEPTED 05 December 2022 PUBLISHED 14 December 2022 Editorial on the Research Topic CITATION Kroschwald S, Arunagiri A, Ventura S, Molecular determinants of protein assemblies in health and disease Ranganathan S and Kohler V (2022), Editorial: Molecular determinants of protein assemblies in health and disease. Protein structure determines its biological function. Conceptually, protein structure Front. Mol. Biosci. 9:1107686. doi: 10.3389/fmolb.2022.1107686 can be classified as folded or “natively-unfolded”. While the defined fold of the former COPYRIGHT dictates a unique function, the latter also called “intrinsically-disordered”, allows © 2022 Kroschwald, Arunagiri, Ventura, polypeptides to engage in a multitude of interactions. Structural features determine Ranganathan and Kohler. This is an also the self-assembly propensity of a protein. Beyond the intrinsic structural aspect, a open-access article distributed under the terms of the Creative Commons protein’s tendency to form higher-order assemblies can be influenced by interacting Attribution License (CC BY). The use, proteinaceous/non-proteinaceous biomolecules. The material properties of assemblies distribution or reproduction in other that are not membrane-enclosed range from liquid to gel-like biomolecular condensates forums is permitted, provided the original author(s) and the copyright to solid-like aggregates. These assemblies can serve to fulfill various biological functions, owner(s) are credited and that the including fostering a reaction, for instance, increasing the activity of actin regulatory original publication in this journal is cited, in accordance with accepted proteins [Science 2019; 363(6431):1093-97], or protecting proteins, e.g. preventing stress- academic practice. No use, distribution induced damage of the translation termination factor Sup35 [Science 2018; 359(6371): or reproduction is permitted which does eaao5654, reviewed in Nature Reviews 2021; 22: 196–213]. Correspondingly, they play not comply with these terms. fundamental roles at cellular and organismal levels. However, if the regulatory mechanisms of these assemblies are error-prone, aggregation-related diseases ensue. These ideas inform us that 1) protein structure, 2) nearby physical interactors, and 3) cellular regulatory elements overall serve as the molecular determinants of protein assemblies. The contributing articles in this Research Topic explore protein structure- function, structure-aggregation, and aggregation-disease relationships. “Exploring the eukaryotic Yip and REEP/Yop superfamily of membrane-shaping adapter proteins (MSAPs): A cacophony or harmony of structure and function?”, by (Angelotti) is a comprehensive review that explores the Yip (Ypt-interacting protein) family proteins, their Frontiers in Molecular Biosciences 01 frontiersin.org Kroschwald et al. 10.3389/fmolb.2022.1107686 binding partners, and cellular functions that mostly encompass occurrence of missense mutations. The paper from Dinamarca et al. membrane shaping. The article epitomizes classic examples of “Synaptic and functional alterations in the development of mutant dealing with and debating topology-to-function links of proteins. huntingtin expressing hiPSC-derived neurons” illustrates how As introduced, proteins have evolved to self-assemble and hereditary disease mutations influence early development acquire new or additional functions. An interesting class of solid- processes of the individual and the way this might impact the like aggregates is amyloids, characterized by a beta-sheet-rich progression of diseases thought to be age-related. fibrillar structure. Amyloids have been shown to have functional Parkinson’s disease, yet another widely studied roles in all kingdoms of life. They are associated with storage in neurodegenerative disorder, is characterized by the intracellular eukaryotes or with biofilm formation to confer antibiotic deposition of amyloid fibrils in the brain tissues. It is proposed that resistance and host colonization in fungi. Involved in the the prefibrillar oligomeric states and not the mature amyloid fibrils latter is adhesin Als5 from Candida albicans, which structural contribute primarily to disease progression, thus being the features are addressed in the article by Golan et al. “Structure and cytotoxic species. Yoo et al. discuss in “Polymorphism in alpha- conservation of amyloid spines from the Candida albicans synuclein oligomers and its implications in toxicity under disease Als5 adhesin” in this Frontiers collection. conditions” how the different shapes of oligomers could Various mechanisms monitor and regulate the formation, differentially contribute to neurotoxicity. properties, dynamics, and dissolution of biomolecular In addition to genetic and internal regulatory mechanisms, condensates and aggregates/amyloids, such as posttranslational several extrinsic factors might modulate the formation of modifications, and the protein quality control system, consisting amyloid states and, ultimately, cross-seeding events. The of molecular chaperones and the protein degradation machinery. review “Microbiome Impact on Amyloidogenesis” by authors The article “The Impact of Hidden Structure on Aggregate Curto et al. summarizes the evidence about how amyloid Disassembly by Molecular Chaperones” by Shoup et al. structures formed by microorganisms could cross-seed the addresses the role of the bi-chaperone (Hsp70/Hsp100) amyloid conformations of human proteins and contribute to disaggregase system from E. coli on aggregates with a the onset of diseases. They also highlight the manipulation of the particular focus on aggregate internal structure. The authors show microbiome as a therapeutic strategy. that aggregates form particles resistant to chaperone-mediated Biomolecular condensates are further gaining center stage as disassembly over time. This transitioning of assemblies into more potential drug targets. Many condensate-forming proteins are solid-like states has been observed for a number of phase-separating enriched in intrinsically disordered regions (IDRs) which are and aggregating proteins and can be associated with a variety of age- often necessary to build up the network of sustaining related diseases. For example, the nucleating core of the Alzheimer’s condensates. However, their unique properties make them disease-related amyloid-beta 42 peptide assembles through a liquid- also prone to aggregate under non-physiologically settings. like state into the characteristic amyloid cross-ß structure. The study Identifying condensates as drug targets holds the potential of by Gordon-Kim et al. about “Polyanion order controls liquid-to-solid impacting these otherwise undruggable IDRs. The current efforts phase transition in peptide/nucleic acid co-assembly” demonstrates are summarized by Patel et al. in “Principles and functions of how nucleic acid structures can externally template this liquid-to- condensate modifying drugs” where they showcase different solid transition. The authors propose mechanisms for templating categories of condensate modifiers or c-mods. events in condensation and amyloid nucleation/propagation events Overall, in this issue, we present a bouquet of novel research plus that might be applicable to other assemblies. timely review articles highlighting protein structure-function Huntington’s disease is another well-characterized connection (Angelotti) and self-assembly including the functional neurodegenerative protein misfolding disorder, caused by role of solid-like assemblies (Golan et al.). Other studies here pathogenic polyQ expansion in the N-terminal huntingtin (HTT) concentrate on the factors including microbiota affecting protein that drives the protein to misfold and aggregate into amyloid amyloidogenesis (Curto et al.), developmental outcomes of fibrils. Many protein misfolding diseases are associated with the aggregation-prone protein mutations (Dinamarca et al.), Frontiers in Molecular Biosciences 02 frontiersin.org Kroschwald et al. 10.3389/fmolb.2022.1107686 proteotoxicity exerted by oligomers (Yoo et al.), and naturally- Conflict of interest occurring aggregation modulators like nucleic acid (Gordon-Kim et al.) or chaperones (Shoup et al.), which help tune the state of these The authors declare that the research was conducted in the assemblies. These key molecular insights along with a report on absence of any commercial or financial relationships that could potential alleviating strategies against aggregation disorders (Patel be construed as a potential conflict of interest. et al.) make this a well-rounded compilation of complementary and unique articles. We believe this topic would be of interest to biophysicists, evolutionary biologists, material scientists, and cell Publisher’s note biologists alike. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated Author contributions organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or SK and AA wrote the primary draft. SV, SR, VK, SK, and AA claim that may be made by its manufacturer, is not guaranteed or edited and finalized the editorial article. endorsed by the publisher. Frontiers in Molecular Biosciences 03 frontiersin.org