Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Ha, Jeung‐Hoi; Tu, Ho-Chou; Wilkens, Stephan; Loh, Stewart N.

doi:10.1016/j.jbc.2021.100446

Cited by 18 publications

(32 citation statements)

References 41 publications

(45 reference statements)

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“…However, in our study, we found obvious amyloid deposits in the interstitium of renal medulla in Patient 1, which were positive for LECT2 in IHC. Genetic analysis of this patient revealed a single base transversion from A to G at position 172 of the LECT2 gene [c.172A>G (p.Ile58Val; NM_002302)], this is a common polymorphism (SNP rs31517) that are thought to be present in all ALECT2 amyloidosis patients ( 16 ). These evidences support that this patient coexisted with ALECT2 amyloidosis.…”

Section: Discussionmentioning

confidence: 94%

Fibrinogen A Alpha-Chain Amyloidosis in Two Chinese Patients

Wang

et al. 2022

Front. Med.

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ObjectivesFibrinogen A alpha-chain amyloidosis (AFib amyloidosis) is the most common form of hereditary renal amyloidosis in the United Kingdom and Europe, but has rarely been reported in Asia. In this study, we reported two AFib amyloidosis patients in China, reviewing the literature and summarizing main characteristics of AFib amyloidosis in Asia.MethodsTwo unrelated Chinese patients were diagnosed with AFib amyloidosis by clinical presentation, renal biopsy, mass spectrometry and DNA sequencing in Peking University First Hospital of China from 2014 to 2016.ResultsBoth of the patients presented with proteinuria, edema and hypertension. Renal biopsies of two patients showed extensive amyloid deposits (Congo red positive) in glomeruli, and focal tubulointerstitial amyloid deposits was also found in patient 1. Besides, hepatic involvement of amyloidosis has been detected by liver biopsy in patient 1. By electron microscopy, randomly arranged fibrils in a diameter of 8–12 nm was identified in mesangial matrix and subendothelial area of glomeruli. Immunohistochemistry demonstrated amyloid deposits were strongly positive for fibrinogen Aα in glomeruli and positive for LECT2 in the interstitium of renal medulla and the liver in Patient 1. Unevenly positive staining for both fibrinogen Aα and ApoA-I were found in Patient 2. Fibrinogen Aα was the most abundant amyloidogenic protein in both patients identified by laser microdissection and mass spectrometry-based proteomic analysis. Genetic analysis revealed the fibrinogen A a-chain gene (FGA) mutation in both patients, including a new deletion mutation [c.1639delA (p.Arg547Glyfs*21; NM_000508)] in Patient 2. Genetic analysis of the LECT2 gene in patient 1 revealed a codon change from ATC to GTC at position 172 [c.172A>G (p.Ile58Val; NM_002302)], which is a common polymorphism (SNP rs31517) in all ALECT2 amyloidosis patients.ConclusionsWe reported two AFib amyloidosis patients in China, one of them coexisted with ALECT2 amyloidosis simultaneously.

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Section: Discussionmentioning

confidence: 94%

Fibrinogen A Alpha-Chain Amyloidosis in Two Chinese Patients

Wang

et al. 2022

Front. Med.

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“…Although regulation of Angpl8 by insulin has been reported [50], free hINS had no impact on either Clec2d or Angpl8 in our study. In contrast, Ca 2+ -dependent actin-binding plastin 1 (Pls1) [51] and amyloidogenic leukocyte-cell-derived chemotaxin 2 [52] (Lect2) were upregulated by free AAC2 and suppressed by the AAC2-hINS complex. Free hINS did not influence these genes.…”

Section: Aac2-hins Improved Cognitive Performance In T1d Mouse Modelsmentioning

confidence: 99%

Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin

et al. 2021

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Diabetes poses a high risk for debilitating complications in neural tissues, regulating glucose uptake through insulin-dependent and predominantly insulin-independent pathways. Supramolecular nanostructures provide a flexible strategy for combinatorial regulation of glycemia. Here, we compare the effects of free insulin to insulin bound to positively charged nanofibers comprised of self-assembling amino acid compounds (AACs) with an antioxidant-modified side chain moiety (AAC2) in both in vitro and in vivo models of type 1 diabetes. Free AAC2, free human insulin (hINS) and AAC2-bound-human insulin (AAC2-hINS) were tested in streptozotocin (STZ)-induced mouse model of type 1 diabetes. AAC2-hINS acted as a complex and exhibited different properties compared to free AAC2 or hINS. Mice treated with the AAC2-hINS complex were devoid of hypoglycemic episodes, had improved levels of insulin in circulation and in the brain, and increased expression of neurotransmitter taurine transporter, Slc6a6. Consequently, treatment with AAC2-hINS markedly advanced both physical and cognitive performance in mice with STZ-induced and genetic type 1 diabetes compared to treatments with free AAC2 or hINS. This study demonstrates that the flexible nanofiber AAC2 can serve as a therapeutic platform for the combinatorial treatment of diabetes and its complications.

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“…Each sensor construct was eluted as a monomeric species from a Superdex S200 Increase size exclusion column (Cytiva) and was judged to be > 95% pure by SDS-PAGE (Figure S5). The circularly permuted FKBP gene was inserted into the Thermoanaerobacter tengcongensis ribose binding protein gene as described by Ha et al 33 The cpFKBP-RBP fusion protein was expressed and purified as described above, after which RBP was cleaved off using HRV-3C protease. Free cpFKBP was recovered by passing the digested solution through a nickel-nitriloacetic acid column to remove free RBP and undigested cpFKBP-RBP.…”

Section: Gene Construction and Protein Purificationmentioning

confidence: 99%

Engineering A Fluorescent Protein Color Switch Using Entropy-driven Beta Strand Exchange

John

Sekhon

et al. 2021

Preprint

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Protein conformational switches are widely used in biosensing. They are typically composed of an input domain (which binds a target ligand) fused to an output domain (which generates an optical readout). A central challenge in designing such switches is to develop mechanisms for coupling the input and output signals via conformational change. Here, we create a biosensor in which binding-induced folding of the input domain drives a conformational shift in the output domain that results in a 6-fold green-to-yellow ratiometric fluorescence change in vitro, and a 35-fold intensiometric fluorescence increase in cultured cells. The input domain consists of circularly permuted FK506 binding protein (cpFKBP) that folds upon binding its target ligand (FK506 or rapamycin). cpFKBP folding induces the output domain, an engineered GFP variant, to replace one of its β-strands (containing T203 and specifying green fluorescence) with a duplicate β-strand (containing Y203 and specifying yellow fluorescence) in an intramolecular exchange reaction. This mechanism employs the loop-closure entropy principle, embodied by folding of the partially disordered cpFKBP domain, to couple ligand binding to the GFP color shift. This proof-of-concept design has the advantages of full genetic encodability, ratiometric or intensiometric response, and potential for modularity. The latter attribute is enabled by circular permutation of the input domain.

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Loss of bound zinc facilitates amyloid fibril formation of leukocyte-cell-derived chemotaxin 2 (LECT2)

Cited by 18 publications

References 41 publications

Fibrinogen A Alpha-Chain Amyloidosis in Two Chinese Patients

Fibrinogen A Alpha-Chain Amyloidosis in Two Chinese Patients

Amino Acid Nanofibers Improve Glycemia and Confer Cognitive Therapeutic Efficacy to Bound Insulin

Engineering A Fluorescent Protein Color Switch Using Entropy-driven Beta Strand Exchange

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