AIP

AIP (AH receptor-interacting protein, also known as XAP2/ARA9) is a ~37 kDa, 330-amino acid FKBP-type immunophilin homolog that functions primarily as a non-enzymatic co-chaperone/scaffold in the HSP90-AHR (aryl hydrocarbon receptor) cytosolic complex. It contains an N-terminal FKBP-type PPIase-like domain that is catalytically inactive (lacking PPIase enzymatic activity and FK506/rapamycin binding) and C-terminal TPR repeats (three TPR motifs plus a terminal alpha-7 helix) that mediate interactions with HSP90 and TOMM20. Cryo-EM structural analysis of the human agonist-bound AHR cytosolic complex (DOI:10.1038/s41467-022-34773-w) reveals AIP/XAP2 acting as a structural brace associated with the HSP90 dimer and the AHR client, with the HSP90 C-terminal MEEVD motif docked into the TPR domain of AIP. AIP has also been reported to facilitate TOMM20-dependent mitochondrial preprotein import and to suppress thermal aggregation of model substrates in vitro, consistent with a holdase-like assay result in this import context rather than a broad protein-folding chaperone role. Beyond the AHR complex, AIP also interacts with phosphodiesterases PDE4A5 and PDE2A3, linking it to localized cAMP regulation and modulation of AHR nuclear translocation. Proteomic studies show AIP co-localizes with HSPA9 in the mitochondrial chaperone network, consistent with mitochondrial chaperone-network association (DOI:10.18632/oncotarget.24183). Germline loss-of-function AIP variants predispose to pituitary neuroendocrine tumors (PitNETs) with incomplete penetrance (~12-30%), behaving as a tumor suppressor with a two-hit model (loss of heterozygosity in tumors). AIP mutations account for ~29% of childhood-onset GH-secreting pituitary tumors presenting as gigantism and ~9% of macroprolactinomas presenting before age 20 (DOI:10.1038/s41574-023-00948-8).

Disorders

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