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A Single-domain Cyclophilin from Leishmania donovani Reactivates Soluble Aggregates of Adenosine Kinase by Isomerase-independent Chaperone Function

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Title A Single-domain Cyclophilin from Leishmania donovani Reactivates
Soluble Aggregates of Adenosine Kinase by Isomerase-independent
Chaperone Function
 
Creator Chakraborty, Anutosh
Das, Ishita
Datta, Rupak
Sen, Banibrata
Bhattacharyya, Debasish
Mandal, Chhabinath
Datta, Alok K
 
Subject Drug Development/Diagnostics & Biotechnology
Infectious Diseases and Immunology
 
Description Disaggregation and reactivation of aggregated proteins
by chaperones is well established. However, little
is known regarding such kind of function of single-domain
small cyclophilins (CyPs). Here we demonstrate
that, with increasing concentrations, fully active adenosine
kinase (AdK) of Leishmania donovani tends to
form soluble aggregates, resulting in inactivation. Using
this inactive enzyme as the substrate, it is shown that a
CyP from L. donovani (LdCyP) alone can cause complete
disaggregation, leading to reactivation of the enzyme.
The reactivating ability of LdCyP remains unaffected
even in the presence of cyclosporin A and macromolecular
crowding agents. The reactivation occurs noncatalytically
and is reversible. A truncated LdCyP, devoid of
88 amino acids from the N terminus, is found to be required
in near stoichiometric proportion to reactivate
AdK, suggesting essentiality of the C-terminal region.
Gel filtration and light-scattering experiments together
with protein cross-linking studies revealed that both
full-length LdCyP and the truncated form directly interact
with AdK and convert oligomeric forms of the enzyme
to monomeric state. Homology modeling studies
suggest that the exposed hydrophobic residues of Ld-
CyP, by interacting with solvent-accessible hydrophobic
surface of AdK, pull apart its aggregated inactive
oligomers to functional monomers. Clearly, the results
are consistent with the interpretation that the higher
efficiency of the truncated LdCyP is most likely due to
increased exposure of the hydrophobic residues on its
surface. These observations, besides establishing L. donovani
AdK as one of the model enzymes to study aggregation-
disaggregation of proteins, raise the possibility
that single-domain small CyPs, under physiological conditions,
may regulate the activity of aggregation-prone
proteins by ensuring their disaggregation.
 
Publisher American Society for Biochemistry and Molecular Biology
 
Date 2002
 
Type Article
PeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/544/1/JOURNAL_OF_BIOLOGICAL_CHEMISTRY__277(49)_47451%2D47460_;2002[1].pdf
Chakraborty, Anutosh and Das, Ishita and Datta, Rupak and Sen, Banibrata and Bhattacharyya, Debasish and Mandal, Chhabinath and Datta, Alok K (2002) A Single-domain Cyclophilin from Leishmania donovani Reactivates Soluble Aggregates of Adenosine Kinase by Isomerase-independent Chaperone Function. The Journal of Biological Chemistry, 277 (49). pp. 47451-47460.
 
Relation http://dx.doi.org/10.1074/jbc.M204827200
http://www.eprints.iicb.res.in/544/