Abstract
Cyclophilins are ubiquitous cis-trans-prolyl isomerases (PPIases) found in all kingdoms of life. Here, we identify a novel family of cyclophilins, termed AquaCyps, which specifically occurs in marine Alphaproteobacteria, but not in related terrestric species. In addition to a canonical PPIase domain, AquaCyps contain large extensions and insertions. The crystal structures of two representatives from Hirschia baltica, AquaCyp293 and AquaCyp300, reveal the formation of a compact domain, the NIC domain, by the N- and C-terminal extensions together with a central insertion. The NIC domain adopts a novel mixed alpha-helical, beta-sheet fold that is linked to the cyclophilin domain via a conserved disulfide bond. In its overall fold, AquaCyp293 resembles AquaCyp300, but the two proteins utilize distinct sets of active site residues, consistent with differences in their PPIase catalytic properties. While AquaCyp293 is a highly active general PPIase, AquaCyp300 is specific for hydrophobic substrate peptides and exhibits lower overall activity.
Highlights
Prolyl cis-trans isomerizations are intrinsically slow reactions, which often determine proteinfolding reactions [1]
We found about 50–60 orthologues of these cyclophilins, and because they are almost exclusively present in organisms living in marine environments, we named this cyclophilin class AquaCyps
We identified a distinct class of cyclophilin peptidyl-prolyl cis-trans isomerase (PPIase) with complex architecture in organisms with a dimorphic, marine lifestyle, such as Hyphomonas, Caulobacter and Hirschia
Summary
Prolyl cis-trans isomerizations are intrinsically slow reactions, which often determine proteinfolding reactions [1]. Cyclophilins are critical for cell responses under stress conditions [10, 11] and are involved in the adaptation to environmental stress, in cell cycle control, signal transduction, and transcriptional regulation [11, 12]. They have been reported to contribute to the virulence of fungal and parasitic pathogens [13,14,15,16,17], and to stress tolerance and pathogenicity of bacteria, such as Legionella pneumophila [18], Enterococcus faecalis [19], and Streptococcus pneumoniae [20]
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