ArticleProtein science : a publication of the Protein Society2017
Disulfide bonds and disorder in granulin-3: An unusual handshake between structural stability and plasticity.
Article in Protein science : a publication of the Protein Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 27 citations in OpenAlex.
- Monospecific antibodies reveal reduction of granulins in frontotemporal dementia caused byMolecular neurodegeneration advances · 2026Article
- The C-terminal region ofAustralian journal of chemistry · 2025Article
- A comprehensive review on structural insights through molecular visualization: tools, applications, and limitations.Journal of molecular modeling · 2025Review
- Granulins rescue inflammation, lysosome dysfunction, lipofuscin, and neuropathology in a mouse model of progranulin deficiency.Cell reports · 2024Article
- Landscape of intrinsically disordered proteins in mental disorder diseases.Computational and structural biotechnology journal · 2024Article
- Reversible Disulfide Bond Cross-Links as Tunable Levers of Phase Separation in Designer Biomolecular Condensates.Journal of the American Chemical Society · 2024Article
- Intrinsically Disordered Proteins: An Overview.International journal of molecular sciences · 2022Review
- Charge and redox states modulate granulin-TDP-43 coacervation toward phase separation or aggregation.Biophysical journal · 2022Article
- Prion-like C-Terminal Domain of TDP-43 and α-Synuclein Interact Synergistically to Generate Neurotoxic Hybrid Fibrils.Journal of molecular biology · 2021Article
- Evidence for a synergistic effect of post-translational modifications and genomic composition of eEF-1α on the adaptation ofEcology and evolution · 2021Article
- Are granulins copper sequestering proteins?Proteins · 2021Article
- Granulins modulate liquid-liquid phase separation and aggregation of the prion-like C-terminal domain of the neurodegeneration-associated protein TDP-43.The Journal of biological chemistry · 2020Article
- Secreted Chaperones in Neurodegeneration.Frontiers in aging neuroscience · 2020Review
- Disorder and cysteines in proteins: A design for orchestration of conformational see-saw and modulatory functions.Progress in molecular biology and translational science · 2020Review
- Cysteine-rich granulin-3 rapidly promotes amyloid-β fibrils in both redox states.The Biochemical journal · 2019Article
- Structure dissection of zebrafish progranulins identifies a well-folded granulin/epithelin module protein with pro-cell survival activities.Protein science : a publication of the Protein Society · 2018Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
Granulins (GRNs) are a family of small (∼6 kDa) proteins generated by the proteolytic processing of their precursor, progranulin (PGRN), in many cell types. Both PGRN and GRNs are implicated in a plethora of biological functions, often in opposing roles to each other. Lately, GRNs have generated significant attention due to their implicated roles in neurodegenerative disorders. Despite their physiological and pathological significance, the structure-function relationships of GRNs are poorly defined. GRNs contain 12 conserved cysteines forming six intramolecular disulfide bonds, making them rather exceptional, even among a few proteins with high disulfide bond density. Solution NMR investigations in the past have revealed a unique structure containing putative interdigitated disulfide bonds for several GRNs, but GRN-3 was unsolvable due to its heterogeneity and disorder. In our previous report, we showed that abrogation of disulfide bonds in GRN-3 renders the protein completely disordered (Ghag et al., Prot Eng Des Sel 2016). In this study, we report the cellular expression and biophysical analysis of fully oxidized, native GRN-3. Our results indicate that both E. coli and human embryonic kidney (HEK) cells do not exclusively make GRN-3 with homogenous disulfide bonds, likely due to the high cysteine density within the protein. Biophysical analysis suggests that GRN-3 structure is dominated by irregular loops held together only by disulfide bonds, which induced remarkable thermal stability to the protein despite the lack of regular secondary structure. This unusual handshake between disulfide bonds and disorder within GRN-3 could suggest a unique adaptation of intrinsically disordered proteins towards structural stability.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.