Peptidyl-prolyl cis-trans isomerase D (PPID)

Peptidyl-prolyl cis-trans isomerase D (PPID), commonly known as Cyclophilin 40 (CyP40), is a 40 kDa member of the immunophilin family that functions as both a peptidyl-prolyl isomerase and a molecular co-chaperone [5, 15, 19]. It is characterized by an N-terminal catalytic domain and a C-terminal tetratricopeptide repeat (TPR) domain, which mediates its interaction with Heat Shock Protein 90 (Hsp90) [12, 15]. This interaction is critical for the assembly, stabilization, and nuclear translocation of steroid hormone receptors, including the androgen, estrogen, and glucocorticoid receptors [5, 15]. In neurodegenerative diseases such as Alzheimer's and Parkinson's, PPID has been identified as a potent protein disaggregase capable of dissolving toxic amyloid aggregates of tau and alpha-synuclein [1, 2, 8]. Conversely, in oncology, PPID is frequently overexpressed and promotes the proliferation of cancer cells, particularly in prostate and breast cancers, by maintaining the activity of oncogenic signaling complexes [5, 11]. While the immunosuppressant drug cyclosporine A binds to PPID, the development of isoform-selective modulators remains a significant therapeutic challenge due to the high structural conservation among cyclophilin family members [6, 10].

Other names

Cyclophilin 40CyP40CYP-40CypD (often confused with mitochondrial PPIF)Rotamase D40 kDa peptidyl-prolyl cis-trans isomeraseCyclophilin-related proteinEstrogen receptor-binding cyclophilin

Inhibition of peptidyl-prolyl isomerase (PPIase) activity [5, 15], disruption of Hsp90-co-chaperone complexes [6], and protein disaggregation of amyloidogenic proteins [1, 8].