Prevention of Domain Swapping Inhibits Dimerization and Amyloid Fibril Formation of Cystatin C

Amyloidogenic proteins like cystatin C and prion proteins have been shown to form dimers by exchange of subdomains of the monomeric proteins. This process, called “three-dimensional domain swapping,” has also been suggested to play a part in the generation of amyloid fibrils. One variant of cystatin C, L68Q cystatin C, is highly amyloidogenic, and persons carrying the corresponding gene suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adult life. The present work describes the production of two variants of wild type and L68Q cystatin C with disulfide bridges at positions selected to inhibit domain swapping without affecting the biological function of the four cystatin C variants as cysteine protease inhibitors. The capacity of the four variant proteins to form dimers was tested and compared with that of wild type and L68Q cystatin C. In contrast to the latter two proteins, all four protein variants stabilized by disulfide bridges were resistant toward the formation of dimers. The capacity of the two stabilized variants of wild type cystatin C to form amyloid fibrils was investigated and found to be reduced by 80% compared with that of wild type cystatin C. In an effort to investigate whether exogenous agents could also suppress the formation of dimers of wild type and L68Q cystatin C, a monoclonal antibody or carboxymethylpapain, an inactivated form of a cysteine protease, was added to systems inducing dimerization of wild type and L68Q cystatin C. It was observed that catalytic amounts of both the monoclonal antibody and carboxymethylpapain could suppress dimerization.

• Publication year

  2004

• Venue

  Journal of Biological Chemistry

• Publication date

  2004-06-04

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/JBC.M402621200PMID 15028721
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Cystatin C-Properties and use as diagnostic marker

  2006cited by this paper
• Immunotherapy as a therapeutic treatment for neurodegenerative disorders

  2003cited by this paper
• Inhibition by Aplidine of the aggregation of the prion peptide PrP 106-126 into beta-sheet fibrils.

  2003cited by this paper
• Protein folding and misfolding

  2003cited by this paper
• Seeded conversion of recombinant prion protein to a disulfide-bonded oligomer by a reduction-oxidation process

  2003cited by this paper
• Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases

  2002cited by this paper
• Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis.

  2002cited by this paper
• Ideas of order for amyloid fibril structure.

  2002cited by this paper
• Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo

  2002cited by this paper
• Human stefin B readily forms amyloid fibrils in vitro.

  2002cited by this paper
• Medicine: Danger — misfolding proteins

  2002cited by this paper
• Therapeutically effective antibodies against amyloid-β peptide target amyloid-β residues 4–10 and inhibit cytotoxicity and fibrillogenesis

  2002cited by this paper
• Crystal structure of the human prion protein reveals a mechanism for oligomerization

  2002cited by this paper
• 3D domain swapping, protein oligomerization, and amyloid formation.

  2001cited by this paper
• The cerebral hemorrhage-producing cystatin C variant (L68Q) in extracellular fluids

  2001cited by this paper
• Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping

  2001cited by this paper
• Trading places

  2001cited by this paper
• Molecular Cloning: A Laboratory Manual

  2001cited by this paper
• Cerebral amyloid angiopathy: An overview

  2000cited by this paper
• Review: history of the amyloid fibril.

  2000cited by this paper
• Hereditary cystatin C amyloid angiopathy

  2000cited by this paper
• Stabilization of human RNase 1 by introduction of a disulfide bond between residues 4 and 118.

  2000cited by this paper
• Gelsolin inhibits the fibrillization of amyloid beta-protein, and also defibrillizes its preformed fibrils.

  2000cited by this paper
• Screening for pharmacologic inhibitors of amyloid fibril formation.

  1999cited by this paper
• Protein misfolding, evolution and disease.

  1999cited by this paper
• Synthesis and evaluation of inhibitors of transthyretin amyloid formation based on the non-steroidal anti-inflammatory drug, flufenamic acid.

  1999cited by this paper
• Evolution of amyloid: what normal protein folding may tell us about fibrillogenesis and disease.

  1999cited by this paper
• Two stable unfolding intermediates of the disease-causing L68Q variant of human cystatin C.

  1998cited by this paper
• Pathologic conformations of prion proteins.

  1998cited by this paper
• Oligomer formation by 3D domain swapping: a model for protein assembly and misassembly.

  1997cited by this paper
• Instability, unfolding and aggregation of human lysozyme variants underlying amyloid fibrillogenesis

  1997cited by this paper
• MOLMOL: a program for display and analysis of macromolecular structures.

  1996cited by this paper
• Folding-related Dimerization of Human Cystatin C (*)

  1996cited by this paper
• 3D domain swapping: A mechanism for oligomer assembly

  1995cited by this paper
• Increased body temperature accelerates aggregation of the Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy.

  1994cited by this paper
• Cystatins.

  1994cited by this paper
• Domain swapping: entangling alliances between proteins.

  1994cited by this paper
• Thioflavine T interaction with synthetic Alzheimer's disease β‐amyloid peptides: Detection of amyloid aggregation in solution

  1993cited by this paper
• Reduction of disulfide bonds in an amyloidogenic Bence Jones protein leads to formation of "amyloid-like" fibrils in vitro.

  1993cited by this paper
• Interaction of recombinant human cystatin C with the cysteine proteinases papain and actinidin.

  1992cited by this paper
• Improved methods for building protein models in electron density maps and the location of errors in these models.

  1991cited by this paper
• High-level expression of active human cystatin C in Escherichia coli.

  1989cited by this paper
• Stabilization of phage T4 lysozyme by engineered disulfide bonds.

  1989cited by this paper
• Interaction of chicken cystatin with inactivated papains.

  1989cited by this paper
• The 2.0 A X‐ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases.

  1988cited by this paper
• Efficient production of native, biologically active human cystatin C by Escherichia coli

  1988cited by this paper
• Production, characterization and use of monoclonal antibodies against the major extracellular human cysteine proteinase inhibitors cystatin C and kininogen.

  1988cited by this paper
• A sensitive and rapid enzyme-linked immunosorbent assay using monoclonal antibodies for simultaneous quantitation of free and IgA-complexed protein HC.

  1985cited by this paper
• Inhibition of cysteine proteinases and dipeptidyl peptidase I by egg-white cystatin.

  1984cited by this paper
• Analysis of gene control signals by DNA fusion and cloning in Escherichia coli.

  1980cited by this paper
• Agarose gel electrophoresis.

  1979cited by this paper
• Quantitation of gamma-trace in human biological fluids: indications for production in the central nervous system.

  1979cited by this paper
• Immunofixation. I. General principles and application to agarose gel electrophoresis.

  1976cited by this paper
• A linear equation that describes the steady-state kinetics of enzymes and subcellular particles interacting with tightly bound inhibitors.

  1972cited by this paper
• 14 Papain and Other Plant Sulfhydryl Proteolytic Enzymes

  1971cited by this paper
• The purification of papain by affinity chromatography.

  1970cited by this paper
• Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4

  1970cited by this paper

• Copper interaction with cystatin C: effects on protein structure and oligomerization

  2024cites this paper
• Identification of a Steric Zipper Motif in the Amyloidogenic Core of Human Cystatin C and Its Use for the Design of Self-Assembling Peptides

  2022cites this paper
• Oligomerization of Human Cystatin C—An Amyloidogenic Protein: An Analysis of Small Oligomeric Subspecies

  2022cites this paper
• In Silico Therapeutic Peptide Design Against Pathogenic Domain Swapped Human Cystatin C Dimer

  2021cites this paper
• In Silico Therapeutic Peptide Design Against Pathogenic Domain Swapped Human Cystatin C Dimer

  2021cites this paper
• Experimental and theoretical study on converting myoglobin into a stable domain-swapped dimer by utilizing a tight hydrogen bond network at the hinge region

  2021cites this paper
• Is amyloid fibrillation related to 3D domain swapping for the C-terminal domain of SARS-CoV main protease?

  2021cites this paper
• NAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients

  2021cites this paper
• Thermodynamic control of domain swapping by modulating helical propensity in the hinge region of myoglobin.

  2020cites this paper
• The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

  2020cites this paper
• Double Domain Swapping in Human γC and γD Crystallin Drives Early Stages of Aggregation

  2020cites this paper
• Kidney-Detrimental Factors and Estimated Glomerular Filtration Rate in Preterm Newborns: The Role of Nutrition

  2020cites this paper
• Cosolvent effects on the growth of amyloid fibrils.

  2020cites this paper
• New Disulphide Bond in Cystatin-Based Protein Scaffold Prevents Domain-Swap-Mediated Oligomerization and Stabilizes the Functionally Active Form

  2019cites this paper
• Stabilized Human Cystatin C Variant L47C/G69C Is a Better Reporter Than the Wild-Type Inhibitor for Characterizing the Thermodynamics of Binding to Cysteine Proteases

  2019cites this paper
• Structural Characterization of Covalently Stabilized Human Cystatin C Oligomers

  2019cites this paper
• NMR and crystallographic structural studies of the extremely stable monomeric variant of human cystatin C with single amino acid substitution

  2019cites this paper
• The identification of discontinuous epitope in the human cystatin C - Monoclonal antibody HCC3 complex.

  2019cites this paper
• Heterodimerizing helices as tools for nanoscale control of the organization of protein-protein and protein-quantum dots.

  2019cites this paper
• Structure, function and engineering of biotechnologically important proteins

  2019cites this paper
• Synthesis and physicochemical studies of amyloidogenic hexapeptides derived from human cystatin C

  2018cites this paper
• Identification and characterization of antibodies elicited by human cystatin C fragment

  2018influential citation
• Stability and kinetics of folding of the domain-swapped dimer of the FOXP3 forkhead domain

  2018cites this paper
• Cyclic trimer of human cystatin C, an amyloidogenic protein - molecular dynamics and experimental studies

  2018cites this paper
• Molecular Dynamics Studies on Amyloidogenic Proteins

  2018cites this paper
• Glycerolipid Headgroups Control Rate and Mechanism of Superoxide Dismutase-1 Aggregation and Accelerate Fibrillization of Slowly Aggregating Amyotrophic Lateral Sclerosis Mutants.

  2018cites this paper
• Cosolvent Effects on the Growth of Protein Aggregates Formed by a Single Domain Globular Protein and an Intrinsically Disordered Protein

  2018cites this paper
• Overall conformation of covalently stabilized domain-swapped dimer of human cystatin C in solution

  2017cites this paper
• Chapter 8 Protein Oligomerization

  2017cites this paper
• Intracellular Trafficking and Regulation of Variant B Cystatin C in Retinal Pigment Epithelial Cells

  2017cites this paper
• Insights into the mechanism of cystatin C oligomer and amyloid formation and its interaction with β-amyloid

  2017cites this paper
• Human cystatin C monomer, dimer, oligomer, and amyloid structures are related to health and disease

  2016cites this paper
• Protein Domain-Swapping Can Be a Consequence of Functional Residues.

  2016cites this paper
• Crystallographic studies on protein misfolding: Domain swapping and amyloid formation in the SH3 domain.

  2016cites this paper
• Understanding protein domain-swapping using structure-based models of protein folding

  2016influential citation
• Epitope location for two monoclonal antibodies against human cystatin C, representing opposite aggregation inhibitory properties

  2016cites this paper
• Isolation and characterization of autoantibodies against human cystatin C

  2016cites this paper
• A review on protein oligomerization process

  2015cites this paper
• Exploring the 'aggregation-prone' core of human Cystatin C: A structural study.

  2015cites this paper
• Conformational stability of the RNP domain controls fibril formation of PABPN1

  2015cites this paper
• Limited Proteolysis Reveals That Amyloids from the 3D Domain-Swapping Cystatin B Have a Non-Native β-Sheet Topology.

  2015cites this paper
• A review on protein oligomerization process

  2015cites this paper
• Fertility Defects in Mice Expressing the L68Q Variant of Human Cystatin C

  2014cites this paper
• Micelle-catalyzed domain swapping in the GlpG rhomboid protease cytoplasmic domain.

  2014cites this paper
• Cystatin C and Alzheimer's Disease

  2014cites this paper
• Micelle-Catalyzed Domain Swapping in the Cytoplasmic Domain of E. coli Rhomboid Protease

  2014cites this paper
• Developmental Regulation of Synthesis and Dimerization of the Amyloidogenic Protease Inhibitor Cystatin C in the Hematopoietic System*

  2014cites this paper
• Cystatin C as a Renal Function Marker for Neonates

  2013cites this paper
• Serum cystatin C during 30 postnatal days is dependent on the postconceptional age in neonates

  2013cites this paper
• Structural characterization of V57D and V57P mutants of human cystatin C, an amyloidogenic protein.

  2013cites this paper
• Steered molecular dynamics simulation of the binding of the β2 and β3 regions in domain-swapped human cystatin C dimer

  2013cites this paper
• Stabilization, Characterization, and Selective Removal of Cystatin C Amyloid Oligomers*

  2013cites this paper
• β(2)-microglobulin amyloidosis.

  2012cites this paper
• Domain swapping and amyloid fibril conformation

  2012cites this paper
• Steered molecular dynamics simulations on the binding of the appendant structure and helix-β2 in domain-swapped human cystatin C dimer

  2012cites this paper
• Influence of point mutations on the stability, dimerization, and oligomerization of human cystatin C and its L68Q variant

  2012cites this paper
• The mammalian DUF59 protein Fam96a forms two distinct types of domain-swapped dimer.

  2012cites this paper
• Identification of the epitope for anti-cystatin

  2011cites this paper
• Identification of the epitope for anti‐cystatin C antibody

  2011influential citation
• Theoretical studies of apolipoprotein interactions

  2011cites this paper
• Cystatin C as a Biomarker in Kidney Disease

  2011cites this paper
• 3D domain swapping - implications for conformational disorders and ways of control

  2011cites this paper
• Mechanisms of amyloid fibril formation – focus on domain‐swapping

  2011cites this paper
• Amyloid-like Fibrils from a Domain-swapping Protein Feature a Parallel, in-Register Conformation without Native-like Interactions*

  2011cites this paper
• High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy

  2011influential citation
• 3dswap-pred: prediction of 3D domain swapping from protein sequence using Random Forest approach.

  2011cites this paper
• Production of Cystatin C Wild Type and Stabilized Mutants

  2010cites this paper
• β2-microglobulin forms 3D domain-swapped amyloid fibrils with disulfide linkages

  2010cites this paper
• Crystal structure of human cystatin C stabilized against amyloid formation

  2010cites this paper
• Domain swapping in materials design

  2010cites this paper
• Structural and Dynamic properties of a new Amyloidogenic chicken cystatin Mutant I108T

  2010cites this paper
• Amyloid fibril formation by human stefins: Structure, mechanism & putative functions.

  2010cites this paper
• Aggregation mechanisms of cystatins: a comparative study of monellin and oryzacystatin.

  2010cites this paper
• Fundamental Structures and Behaviors of Proteins

  2010cites this paper
• Hinge-loop mutation can be used to control 3D domain swapping and amyloidogenesis of human cystatin C.

  2010cites this paper
• Governing the monomer-dimer ratio of human cystatin c by single amino acid substitution in the hinge region.

  2009cites this paper
• The Testatin/Cres subgroup of family 2 cystatins in sexual development

  2009cites this paper
• The mechanism of amyloid‐fibril formation by stefin B: Temperature and protein concentration dependence of the rates

  2009cites this paper
• The role of the Val57 amino‐acid residue in the hinge loop of the human cystatin C. Conformational studies of the beta2‐L1‐beta3 segments of wild‐type human cystatin C and its mutants

  2009cites this paper
• A unifying hypothesis for explaining the mechanism of amyloid formation under conditions of increased oxidative stress

  2008cites this paper
• Sequence and structural determinants of strand swapping and binding affinity in cadherin domains

  2008cites this paper
• Molecular Dynamics Simulations To Investigate the Domain Swapping Mechanism of Human Cystatin C

  2008cites this paper
• Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants

  2008cites this paper
• Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo.

  2008cites this paper
• Self-assembly of human latexin into amyloid-like oligomers

  2007cites this paper
• Extracellular quality control in the epididymis.

  2007cites this paper
• Amyloid fibril formation by human stefin B: influence of pH and TFE on fibril growth and morphology

  2007cites this paper
• Amyloid peptides and proteins in review.

  2007cites this paper
• Three-dimensional domain swapping and its relevance to conformational diseases

  2007cites this paper
• Protease Inhibitors and their Involvement in Neurological Disorders

  2007cites this paper
• Oryzacystatin-II, a cystatin from rice (Oryza sativa L. japonica), is a dimeric protein: possible involvement of the interconversion between dimer and monomer in the regulation of the reactivity of oryzacystatin-II.

  2007cites this paper
• Cystatin C reduces the in vitro formation of soluble Aβ1‐42 oligomers and protofibrils

  2007cites this paper
• Protein reconstitution and three‐dimensional domain swapping: Benefits and constraints of covalency

  2007cites this paper
• Molecular Dynamics Simulations of Human Cystatin C and Its L68Q Varient to Investigate the Domain Swapping Mechanism

  2007cites this paper
• Fibrillogenic Oligomers of Human Cystatin C Are Formed by Propagated Domain Swapping*

  2007cites this paper
• Domain swapping as a molecular mechanism in amyloidosis

  2007cites this paper
• Runaway domain swapping in amyloid-like fibrils of T7 endonuclease I.

  2006cites this paper
• Deposition diseases and 3D domain swapping.

  2006cites this paper
• Structural models of amyloid-like fibrils.

  2006cites this paper
• Prevention of amyloid fibril formation of amyloidogenic chicken cystatin by site‐specific glycosylation in yeast

  2006influential citation