Abstract
The two classical immunophilin families, found essentially in all living cells, are: cyclophilin (CYN) and FK506-binding protein (FKBP). We previously reported a novel class of immunophilins that are natural chimera of these two, which we named dual-family immunophilin (DFI). The DFIs were found in either of two conformations: CYN-linker-FKBP (CFBP) or FKBP-3TPR-CYN (FCBP). While the 3TPR domain can serve as a flexible linker between the FKBP and CYN modules in the FCBP-type DFI, the linker sequences in the CFBP-type DFIs are relatively short, diverse in sequence, and contain no discernible motif or signature. Here, I present several lines of computational evidence that, regardless of their primary structure, these CFBP linkers are intrinsically disordered. This report provides the first molecular foundation for the model that the CFBP linker acts as an unstructured, flexible loop, allowing the two flanking chaperone modules function independently while linked in cis, likely to assist in the folding of multisubunit client complexes.
Highlights
Immunophilins of the CYN and FK506binding protein (FKBP) families are ubiquitous chaperones that facilitate and regulate the folding of client proteins [1,2]
We showed that the dual-family immunophilin (DFI) chaperones occur either as CYN-linker-FKBP or as FKBP-linkerCYN, which were given the distinguishing acronyms of CFBP and FK506- and cyclosporin-binding protein (FCBP), respectively, to indicate the domain order [4]
I reasoned that the linkers hold the key to the properties and features of the DFIs that make them unique and distinct from the individual CYN and FKBP chaperones, separate homologs of which occur in the same organisms
Summary
Immunophilins of the CYN and FKBP families are ubiquitous chaperones that facilitate and regulate the folding of client proteins [1,2]. Our recent survey showed that the DFIs are found in select microbes that are primarily extremophiles and aquatic, and suggested a model in which the double-pronged chaperoning role of a DFI is essential in simultaneous folding of multisubunit protein complexes, especially in rapidly denaturing, high-stress environments [5]. Since both CYN and FKBP domains are relatively well-known I have focused attention on the linker sequence connecting them, which is responsible for the creation of the chimera. The current study presents a comprehensive analysis of linkers in 277 CFBP sequences, mined from GenBank, and documents that they possess the hallmarks of “intrinsic disorder” (ID), a recently appreciated feature of protein sequences that are natively unstructured and often constitute regions of intramolecular flexibility [9,10,11,12,13,14]
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