Protein Self-Assembly in Diseases and Function

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 565

Special Issue Editors


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Guest Editor
Department of Biological Sciences, East Tennessee State University, Johnson City, TN, USA
Interests: protein folding; protein aggregation; amyloid; diabetes; proteinopathies; proteostasis; protein trafficking; ER quality control; disulfide bonds; autophagy
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Guest Editor
Max Plack Institute for the Physics of Complex Systems, Dresden, Germany
Interests: biomolecular simulations; computational biophysics; self-assembly; biomolecular condensates

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Guest Editor
Center of Alzheimer's and Neurodegenerative Diseases, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
Interests: amyloid; protein misfolding; neurodegeneration; systemic amyloidosis; biophysics

Special Issue Information

Dear Colleagues,

Protein self-assembly is central to the pathogenesis of a wide range of degenerative diseases, including Alzheimer's, Parkinson's, and type 2 diabetes. These aberrant protein conformations (called amyloids) can disrupt cellular homeostasis, leading to cell death and tissue degeneration. Over the past two decades, there has been accumulating evidence of functional amyloids involved in a beneficial role in the host organism rather than causing diseases. This idea has been further reinforced with the emergence of biomolecular condensation events in cells that are transient (mostly functional) self-assembled structures involving proteins and other biomolecules like RNA. This Special Issue seeks to illuminate the underlying mechanisms driving protein aggregation and condensation. We aim to address the following critical questions: (1) Why are certain cell types more susceptible to proteinopathies than others? (2) What molecular factors underly the formation of biomolecular condensates? (3) How do cells respond to the beneficial versus toxic effects of aggregated proteins? By understanding these fundamental processes, novel therapeutic targets can be identified to promote or prevent protein self-assembly in cells. We invite submissions of original research and review articles that contribute to our understanding of protein folding, misfolding, and aggregation.

Dr. Anoop Arunagiri
Dr. Srivastav Ranganathan
Dr. Maria del Carmen Fernandez Ramirez
Guest Editors

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Keywords

  • protein folding
  • protein aggregation
  • amyloids
  • biomolecular condensates

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Published Papers (1 paper)

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Research

17 pages, 6352 KiB  
Article
The B22 Dilemma: Structural Basis for Conformational Differences in Proinsulin B-Chain Arg22 Mutants
by Srivastav Ranganathan and Anoop Arunagiri
Biomolecules 2025, 15(4), 577; https://doi.org/10.3390/biom15040577 - 12 Apr 2025
Viewed by 299
Abstract
Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)’s role in proinsulin stability [...] Read more.
Proinsulin has three distinct regions: the well-folded A- and B-chains and the dynamic disordered C-peptide. The highly conserved B-chain is a hotspot for diabetes-associated mutations, including the severe loss-of-function R(B22)Q mutation linked to childhood-onset diabetes. Here, we explore R(B22)’s role in proinsulin stability using AlphaFold-predicted structures and metadynamics simulations to achieve enhanced sampling of the free energy landscape. Our results show that R(B22) stabilizes proinsulin by interacting with N86. Substituting R(B22) with E or Q disrupts this interaction, increasing conformational flexibility. The R(B22)Q variant exhibits a flattened free energy landscape, favoring unfolded states. Additional substitutions, including Gly, Ala, Lys, Tyr, Asp, and Phe, destabilize proinsulin to varying extents by weakening hydrogen bonding. Disrupting the R(B22)–N86 interaction broadly reduces inter-chain contacts, raising the risk of aggregation-prone states. Given the link between R(B22) mutations and diabetes, our study provides crucial molecular insights into proinsulin instability. These findings highlight the role of key inter-domain (A-Chain–B-chain, B-Chain–C-peptide, and A-Chain–C-peptide) interactions in maintaining protein structures and the implications this has for understanding disease-associated proinsulin variants. Full article
(This article belongs to the Special Issue Protein Self-Assembly in Diseases and Function)
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