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

Biopolymers ◽  
2009 ◽  
Vol 91 (5) ◽  
pp. 373-383 ◽  
Author(s):  
Sylwia Rodziewicz-Motowidło ◽  
Justyna Iwaszkiewicz ◽  
Renata Sosnowska ◽  
Paulina Czaplewska ◽  
Emil Sobolewski ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cystatin C ◽  
Amino Acid Residue ◽  
Wild Type ◽  
Conformational Studies ◽  
Human Cystatin C ◽  
Human Cystatin

scholarly journals Governing the monomer-dimer ratio of human cystatin c by single amino acid substitution in the hinge region.

2009 ◽  
Vol 56 (3) ◽  
Author(s):  
Aneta Szymańska ◽  
Adrianna Radulska ◽  
Paulina Czaplewska ◽  
Anders Grubb ◽  
Zbigniew Grzonka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cystatin C ◽  
Amino Acid Substitution ◽  
Mutational Analysis ◽  
Three Dimensional ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Human Cystatin C ◽  
Human Cystatin

Three dimensional domain swapping is one of the mechanisms involved in formation of insoluble aggregates of some amyloidogenic proteins. It has been proposed that proteins able to swap domains may share some common structural elements like conformationally constrained flexible turns/loops. We studied the role of loop L1 in the dimerization of human cystatin C using mutational analysis. Introduction of turn-favoring residues such as Asp or Asn into the loop sequence (in position 57) leads to a significant reduction of the dimer fraction in comparison with the wild type protein. On the other hand, introduction of a proline residue in position 57 leads to efficient dimer formation. Our results confirm the important role of the loop L1 in the dimerization process of human cystatin C and show that this process can be to some extent governed by single amino acid substitution.

Correction to: 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

2019 ◽  
Vol 38 (5) ◽  
pp. 608-608
Author(s):  
David O. Tovar-Anaya ◽  
L. Irais Vera-Robles ◽  
M. Teresa Vieyra-Eusebio ◽  
Ponciano García-Gutiérrez ◽  
Francisco Reyes-Espinosa ◽  
...  
Keyword(s):  
Cystatin C ◽  
Cysteine Proteases ◽  
Wild Type ◽  
Human Cystatin C ◽  
Human Cystatin

Interaction of serum amyloid A with human cystatin C-assessment of amino acid residues crucial for hCC-SAA formation (part II)

2013 ◽  
Vol 26 (9) ◽  
pp. 415-425 ◽  
Author(s):  
Marta Spodzieja ◽  
Monika Rafalik ◽  
Aneta Szymańska ◽  
Aleksandra S. Kołodziejczyk ◽  
Paulina Czaplewska
Keyword(s):  
Amino Acid ◽  
Cystatin C ◽  
Serum Amyloid A ◽  
Serum Amyloid ◽  
Amino Acid Residues ◽  
Amyloid A ◽  
Human Cystatin C ◽  
Human Cystatin

scholarly journals Importance of the evolutionarily conserved glycine residue in the N-terminal region of human cystatin C (Gly-11) for cysteine endopeptidase inhibition

1993 ◽  
Vol 291 (1) ◽  
pp. 123-129 ◽  
Author(s):  
A Hall ◽  
H Dalbøge ◽  
A Grubb ◽  
M Abrahamson
Keyword(s):  
Cystatin C ◽  
Equilibrium Constants ◽  
Terminal Segment ◽  
Site Directed Mutagenesis ◽  
Side Chains ◽  
Wild Type ◽  
Human Cystatin C ◽  
Evolutionarily Conserved ◽  
Cysteine Endopeptidases ◽  
Human Cystatin

Human cystatin C variants in which the evolutionarily conserved Gly-11 residue has been replaced by residues with positively charged (Arg), negatively charged (Glu), bulky hydrophobic (Trp), or small (Ser or Ala) side-chains have been produced by site-directed mutagenesis and expression in Escherichia coli. The five variants were isolated and structurally verified. Their inhibitory properties were compared with those of wild-type recombinant cystatin C by determination of the equilibrium constants for dissociation (Ki) of their complexes with the cysteine endopeptidases papain and human cathepsin B and with the cysteine exopeptidase dipeptidyl peptidase I. The Ser-11 and Ala-11 cystatin C variants displayed Ki values for the two endopeptidases that were approx. 20-fold higher than those of wild-type cystatin C, while the corresponding values for the Trp-11. Arg-11 and Glu-11 variants were increased by a factor of about 2000. In contrast, the Ki values for the interactions of all five variants with the exopeptidase differed from that of wild-type cystatin C by a factor of less than 10. Wild-type cystatin C and the Ser-11, Ala-11 and Glu-11 variants were incubated with neutrophil elastase, which in all cases resulted in the rapid hydrolysis of a single peptide bond, between amino acid residues 10 and 11. The Ki values for the interactions with papain of these three N-terminal-decapeptide-lacking cystatin C variants were 20-50 nM, just one order of magnitude higher than the value for N-terminally truncated wild-type cystatin C, which in turn was similar to the corresponding values for the full-length Glu-11, Arg-11 and Trp-11 variants. These data indicate that the crucial feature of the conserved Gly residue in position 11 of wild-type cystatin C is that this residue, devoid of a side-chain, will allow the N-terminal segment of cystatin C to adopt a conformation suitable for interaction with the substrate-binding pockets of cysteine endopeptidases, resulting in high-affinity binding and efficient inhibition. The functional properties of the remaining part of the proteinase contact area, which is built from more C-terminal inhibitor segments, are not significantly affected even when amino acids with bulky or charged side-chains replace the Gly-11 residue of the N-terminal segment.

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

2019 ◽  
Vol 38 (5) ◽  
pp. 598-607
Author(s):  
David O. Tovar-Anaya ◽  
L. Irais Vera-Robles ◽  
M. Teresa Vieyra-Eusebio ◽  
Ponciano García-Gutiérrez ◽  
Francisco Reyes-Espinosa ◽  
...  
Keyword(s):  
Cystatin C ◽  
Cysteine Proteases ◽  
Wild Type ◽  
Human Cystatin C ◽  
Human Cystatin

scholarly journals Distinct properties of wild-type and the amyloidogenic human cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type

2001 ◽  
Vol 77 (2) ◽  
pp. 628-637 ◽  
Author(s):  
Miguel Calero ◽  
Monika Pawlik ◽  
Claudio Soto ◽  
Eduardo M. Castaño ◽  
Einar M. Sigurdsson ◽  
...  
Keyword(s):  
Cystatin C ◽  
Cerebral Hemorrhage ◽  
Wild Type ◽  
Human Cystatin C ◽  
Human Cystatin

Modulation of phagocytosis-associated respiratory burst by human cystatin C: Role of the N-terminal tetrapeptide LysProProArg

1990 ◽  
Vol 188 (1) ◽  
pp. 16-22 ◽  
Author(s):  
J. Leung-Tack ◽  
C. Tavera ◽  
M.C. Gensac ◽  
J. Martinez ◽  
A. Colle
Keyword(s):  
Cystatin C ◽  
Respiratory Burst ◽  
Human Cystatin C ◽  
Human Cystatin

Biochemistry and Clinical Role of Human Cystatin C

2004 ◽  
Vol 41 (5-6) ◽  
pp. 467-550 ◽  
Author(s):  
Michele Mussap ◽  
Mario Plebani
Keyword(s):  
Cystatin C ◽  
Clinical Role ◽  
Human Cystatin C ◽  
Human Cystatin

scholarly journals NMR and crystallographic structural studies of the extremely stable monomeric variant of human cystatin C with single amino acid substitution

FEBS Journal ◽  
2019 ◽  
Vol 287 (2) ◽  
pp. 361-376 ◽  
Author(s):  
Martyna Maszota‐Zieleniak ◽  
Przemyslaw Jurczak ◽  
Marta Orlikowska ◽  
Igor Zhukov ◽  
Dominika Borek ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cystatin C ◽  
Amino Acid Substitution ◽  
Single Amino Acid Substitution ◽  
Single Amino Acid ◽  
Structural Studies ◽  
Human Cystatin C ◽  
Human Cystatin

scholarly journals Human cystatin C. role of the N-terminal segment in the inhibition of human cysteine proteinases and in its inactivation by leucocyte elastase

1991 ◽  
Vol 273 (3) ◽  
pp. 621-626 ◽  
Author(s):  
M Abrahamson ◽  
R W Mason ◽  
H Hansson ◽  
D J Buttle ◽  
A Grubb ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cystatin C ◽  
Cysteine Proteinase ◽  
Terminal Segment ◽  
Cysteine Proteinase Inhibitor ◽  
Cathepsin H ◽  
Leucocyte Elastase ◽  
Human Cystatin C ◽  
Binding Pockets ◽  
Human Cystatin

Leucocyte elastase in catalytic amounts was observed to rapidly cleave the Val-10-Gly-11 bond of the human cysteine-proteinase inhibitor cystatin C at neutral pH. The resulting modified inhibitor had size and amino acid composition consistent with a cystatin C molecule devoid of the N-terminal Ser-1-Val-10 decapeptide. Leucocyte-elastase-modified cystatin C had more than 240-fold lower affinity than native cystatin C for papain. Removal of the N-terminal decapeptide of human cystatin C also decreased inhibition of human cathepsins B and L by three orders of magnitude, but decreased inhibition of cathepsin H by only 5-fold. A tripeptidyldiazomethane analogue of of the N-terminal portion of cystatin C was a good inhibitor of cathepsins B and L but a poor inhibitor of cathepsin H. It therefore appears that amino acid side chains of the N-terminal segment of cystatin C bind in the substrate-binding pockets of cathepsins B and L but not in those of cathepsin H. It is argued that the N-terminal cystatin C interaction with cathepsin B is physiologically important and hence that leucocyte elastase could have a function as a regulator of extracellular cysteine-proteinase inhibitory activity at sites of inflammation.

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