Delving into the amyloidogenic core of human leukocyte chemotactic factor 2

Tsiolaki, Paraskevi L.; Nasi, Georgia I.; Baltoumas, Fotis A.; Fishman, Shannon; Tu, Ho-Chou; Iconomidou, Vassiliki A.

doi:10.1016/j.jsb.2019.06.001

Cited by 8 publications

(6 citation statements)

References 75 publications

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, this sequence has not been predicted by previous work to form amyloid fibrils. However, other studies identified the regions immediately preceding and following it as possible amyloidogenic segments 20 , and the newly identified core segment is predicted to form steric zipper structures by the amyloid-prediction algorithm in ZipperDB 25 (Figure S1A). While a significant fraction of the LECT2 sequence is predicted to be amyloidogenic, much of the protein's globular fold is stabilized by three disulfide bonds, two in the N-terminal region and one in C-terminal region (Figure 2A).…”

Section: Discussionmentioning

confidence: 99%

“…This mutation appears to be important, but not sufficient for inducing amyloid formation, and does not destabilize the metal binding properties of the functional protein; accordingly, its role in amyloid conversion remains unclear 18 . Amyloidogenic segments of LECT2 have been identified, and predicted amyloid-forming LECT2 peptides assemble into amyloid-like fibrils in isolation 20 . However, the identity of the LECT2 amyloid core remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core

Richards

Flores

Zink

et al. 2023

Preprint

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ALECT2 is a type of systemic amyloidosis caused by deposition of the leukocyte cell-derived chemotaxin-2 (LECT2) protein in the form of fibrils. In ALECT2, LECT2 fibril deposits can be found in the glomerulus, resulting in renal failure. Affected patients lack effective treatment options outside of renal transplant or dialysis. While the structure of LECT2 in its globular form has been determined by X-ray crystallography, structures of LECT2 amyloid fibrils remain unknown. Using single particle cryo-EM, we now find that human LECT2 forms robust twisting fibrils with canonical amyloid features. At their core, LECT2 fibrils contain two mating protofilaments, the ordered core of each protofilament spans residues 55-75 of the LECT2 sequence. The overall geometry of the LECT2 fibril displays features in line with other pathogenic amyloids. Its core is tightly packed and stabilized by a network of hydrophobic contacts and hydrogen-bonded uncharged polar residues, while its outer surface displays several charged residues. The robustness of LECT2 fibril cores is illustrated by their limited dissolution in 3M urea and their persistence after treatment with proteinase K. As such, the LECT2 fibril structure presents a potential new target for treatments against ALECT2.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core

Richards

Flores

Zink

et al. 2023

Preprint

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“…Specifically, the routine “Peptide docking” and its subroutine “multimer” were used to create our systems. The simulation boxes contained five (5) copies of each peptide-analogue in random conformations, previously shown to be an efficient number of copies for self-assembly simulations [ 36 , 37 ]. The generated clusters were evaluated with the balanced scoring scheme.…”

Section: Methodsmentioning

confidence: 99%

Bacterial Lectin FimH and Its Aggregation Hot-Spots: An Alternative Strategy against Uropathogenic Escherichia coli

et al. 2023

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Type I fimbriae are the main adhesive organelles of uropathogenic Escherichia coli (UPEC), consisting of four different subunits. Their component with the most important role in establishing bacterial infections is the FimH adhesin located at the fimbrial tip. This two-domain protein mediates adhesion to host epithelial cells through interaction with terminal mannoses on epithelial glycoproteins. Here, we propose that the amyloidogenic potential of FimH can be exploited for the development of therapeutic agents against Urinary Tract Infections (UTIs). Aggregation-prone regions (APRs) were identified via computational methods, and peptide-analogues corresponding to FimH lectin domain APRs were chemically synthesized and studied with the aid of both biophysical experimental techniques and molecular dynamic simulations. Our findings indicate that these peptide-analogues offer a promising set of antimicrobial candidate molecules since they can either interfere with the folding process of FimH or compete for the mannose-binding pocket.

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“…The abovementioned results suggested a model in which two perturbants, zinc loss and agitation-induced shear, destabilize and distort (respectively) the LECT2 structure such that a buried amyloidogenic sequence (potentially residues 52–88) ( 8 , 9 ) becomes transiently exposed. Hydrodynamic shear has been shown to induce amyloid formation of Alzheimer Aβ peptides ( 10 , 11 , 12 , 13 ), β-lactoglobulin ( 14 , 15 , 16 ), insulin ( 16 , 17 , 18 , 19 , 20 ), α-synuclein ( 21 , 22 , 23 ), apolipoprotein C-II ( 24 ), superoxide dismutase ( 25 ), antibodies ( 26 ), and other proteins.…”

mentioning

confidence: 99%

Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis

Ha,

Xu,

Sekhon

et al. 2024

Journal of Biological Chemistry

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Delving into the amyloidogenic core of human leukocyte chemotactic factor 2

Cited by 8 publications

References 75 publications

Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core

Cryo-EM Structure of a Human LECT2 Amyloid Fibril Reveals a Network of Polar Ladders at its Core

Bacterial Lectin FimH and Its Aggregation Hot-Spots: An Alternative Strategy against Uropathogenic Escherichia coli

Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis

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