Abstract
Cyclophilins are a subgroup of highly conserved protein family immunophilins which are peptidyl-prolyl isomerases that interconvert between the cis and trans positions. They can act as chaperones in maintaining conformational quality control of proteomes. They are structurally conserved throughout evolution and have been found in mammals, plants, insects, fungi, and bacteria. They share a common fold architecture consisting of 8 antiparallel beta sheets and two alpha helices that pack against the sheets. They exist in the cellular compartment of most tissues and encode special functions. Intracellular Cyclophilins are secreted from cells in response to inflammatory stimuli and can mediate intercellular communication. Pro-inflammatory signals may be stimulated by extracellular Cyclophilin. Overexpression of Cyclophilins can contribute to pathological conditions. Cyclophilins are involved in the pathogenesis of viral infection, neurodegenerative diseases, ageing and cancer. Exhibiting several molecular functions, Cyclophilins can bind to cyclosporine and calcium-dependent ser/thr Calcineurin and has been used to describe the immunosuppressive action of cyclosporine. Cyclophilin can stabilize the cis-trans conformation transition state and speed up isomerization steps in protein folding. This process is important in the assembly of multiple domain proteins. Their existence as foldases and molecular chaperones enable them to be able to assist in the covalent folding or unfolding and the assembly or disassembly of other macromolecular structures.
Highlights
Cyclophilins are a subgroup of large immunophilins protein family
While FK506-binding proteins (FKBPs) has five β strands wrapped around a short alpha-helix forming a conical shape with a hydrophobic groove to which FK506 and peptidyl-prolyl isomerases (PPIase) substrates bind
cyclosporine A (CsA) and FK506 are depicted in ball-and-stick representations; CnA is in yellow; CnB, red; Cyp, green; FKBP, blue; and Ca2+ ions, cyan balls
Summary
Cyclophilins are a subgroup of large immunophilins protein family. Immunophilins are cytosolic peptidyl-prolyl isomerases that interconvert between the cis and trans positions endogenously. The peptidyl-prolyl cis-trans isomerase family include the cyclosporine-binding cyclophilins (Cyps) and FK506-binding proteins (FKBPs). The Cyps and FKBPs both exhibit the peptidyl-prolyl isomerases or rotamase activity and generally accelerates the changes in conformation between the cis and trans forms of the Xaa-Pro peptide bond during the folding of a substrate protein in-vitro [1]. Sequence alignments analysis of the Cyp and FKBPs from different phyla show that their PPIase activity site and macrolide binding cavity amino acid residues remain well preserved in the majority of them but their sequences diverge which suggests that the spatial structures and functions of each group of PPIases remain conserved [6]. The human Cyp have long carboxyl-terminal (TPR) repeats; they associate functionally with homologs of heat-shock proteins and other protein chaperones Regardless of their origin, Cyps structural conservation throughout evolution and the PPIase activity of members underlines the importance of their enzymatic reaction. Inference can be made from the sequence and structural diversity in this region for different binding partners [20]
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