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

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      1 , 2 , 1 , 1 ,
      The Journal of Biological Chemistry
      American Society for Biochemistry and Molecular Biology
      ALECT2, misfolding, aggregation, metal binding, amyloidosis, ALECT2, amyloidosis of leukocyte-cell-derived chemotaxin 2, apoLECT2, leukocyte-cell-derived chemotaxin 2 lacking its single bound zinc ion, BCA, bicinchoninic assay, Cm, midpoint of chemical denaturation, GdnHCl, guanidine hydrochloride, HSQC, heteronuclear single-quantum correlation, IDA, iminodiacetic acid, Kd, equilibrium dissociation constant of zinc binding, koff, zinc dissociation rate, LECT2, leukocyte-cell-derived chemotaxin 2, SA, systemic amyloidosis, SEC, size-exclusion chromatography, ThT, thioflavin T, TIE, tyrosine kinase with immunoglobulin-like and EGF-like domains, Tm, midpoint of thermal denaturation

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          Abstract

          Aggregation of the circulating protein leukocyte-cell-derived chemotaxin 2 (LECT2) causes amyloidosis of LECT2 (ALECT2), one of the most prevalent forms of systemic amyloidosis affecting the kidney and liver. The I40V mutation is thought to be necessary but not sufficient for ALECT2, with a second, as-yet undetermined condition being required for the disease. EM, X-ray diffraction, NMR, and fluorescence experiments demonstrate that LECT2 forms amyloid fibrils in vitro in the absence of other proteins. Removal of LECT2’s single bound Zn 2+ appears to be obligatory for fibril formation. Zinc-binding affinity is strongly dependent on pH: 9–13 % of LECT2 is calculated to exist in the zinc-free state over the normal pH range of blood, with this fraction rising to 80 % at pH 6.5. The I40V mutation does not alter zinc-binding affinity or kinetics but destabilizes the zinc-free conformation. These results suggest a mechanism in which loss of zinc together with the I40V mutation leads to ALECT2.

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          Common core structure of amyloid fibrils by synchrotron X-ray diffraction.

          Tissue deposition of normally soluble proteins as insoluble amyloid fibrils is associated with serious diseases including the systemic amyloidoses, maturity onset diabetes, Alzheimer's disease and transmissible spongiform encephalopathy. Although the precursor proteins in different diseases do not share sequence homology or related native structure, the morphology and properties of all amyloid fibrils are remarkably similar. Using intense synchrotron sources we observed that six different ex vivo amyloid fibrils and two synthetic fibril preparations all gave similar high-resolution X-ray fibre diffraction patterns, consistent with a helical array of beta-sheets parallel to the fibre long axis, with the strands perpendicular to this axis. This confirms that amyloid fibrils comprise a structural superfamily and share a common protofilament substructure, irrespective of the nature of their precursor proteins. Copyright 1997 Academic Press Limited.
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            The biological inorganic chemistry of zinc ions☆

            The solution and complexation chemistry of zinc ions is the basis for zinc biology. In living organisms, zinc is redox-inert and has only one valence state: Zn(II). Its coordination environment in proteins is limited by oxygen, nitrogen, and sulfur donors from the side chains of a few amino acids. In an estimated 10% of all human proteins, zinc has a catalytic or structural function and remains bound during the lifetime of the protein. However, in other proteins zinc ions bind reversibly with dissociation and association rates commensurate with the requirements in regulation, transport, transfer, sensing, signalling, and storage. In contrast to the extensive knowledge about zinc proteins, the coordination chemistry of the “mobile” zinc ions in these processes, i.e. when not bound to proteins, is virtually unexplored and the mechanisms of ligand exchange are poorly understood. Knowledge of the biological inorganic chemistry of zinc ions is essential for understanding its cellular biology and for designing complexes that deliver zinc to proteins and chelating agents that remove zinc from proteins, for detecting zinc ion species by qualitative and quantitative analysis, and for proper planning and execution of experiments involving zinc ions and nanoparticles such as zinc oxide (ZnO). In most investigations, reference is made to zinc or Zn2+ without full appreciation of how biological zinc ions are buffered and how the d-block cation Zn2+ differs from s-block cations such as Ca2+ with regard to significantly higher affinity for ligands, preference for the donor atoms of ligands, and coordination dynamics. Zinc needs to be tightly controlled. The interaction with low molecular weight ligands such as water and inorganic and organic anions is highly relevant to its biology but in contrast to its coordination in proteins has not been discussed in the biochemical literature. From the discussion in this article, it is becoming evident that zinc ion speciation is important in zinc biochemistry and for biological recognition as a variety of low molecular weight zinc complexes have already been implicated in biological processes, e.g. with ATP, glutathione, citrate, ethylenediaminedisuccinic acid, nicotianamine, or bacillithiol.
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              Amyloid beta-protein assembly and Alzheimer disease.

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                Author and article information

                Contributors
                Journal
                J Biol Chem
                J Biol Chem
                The Journal of Biological Chemistry
                American Society for Biochemistry and Molecular Biology
                0021-9258
                1083-351X
                20 February 2021
                2021
                20 February 2021
                : 296
                : 100446
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
                [2 ]Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
                Author notes
                []For correspondence: Stewart N. Loh lohs@ 123456upstate.edu
                Article
                S0021-9258(21)00219-2 100446
                10.1016/j.jbc.2021.100446
                8039541
                33617884
                5800b821-0dc5-4792-9ba4-ff0f91e38266
                © 2021 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 11 January 2021
                : 5 February 2021
                Categories
                Accelerated Communication

                Biochemistry
                alect2,misfolding,aggregation,metal binding,amyloidosis,alect2, amyloidosis of leukocyte-cell-derived chemotaxin 2,apolect2, leukocyte-cell-derived chemotaxin 2 lacking its single bound zinc ion,bca, bicinchoninic assay,cm, midpoint of chemical denaturation,gdnhcl, guanidine hydrochloride,hsqc, heteronuclear single-quantum correlation,ida, iminodiacetic acid,kd, equilibrium dissociation constant of zinc binding,koff, zinc dissociation rate,lect2, leukocyte-cell-derived chemotaxin 2,sa, systemic amyloidosis,sec, size-exclusion chromatography,tht, thioflavin t,tie, tyrosine kinase with immunoglobulin-like and egf-like domains,tm, midpoint of thermal denaturation

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