AIP TPR domain in complex with human Hsp90 peptide
[AIP_HUMAN] Acromegaly;Familial prolactinoma. Defects in AIP are a cause of growth hormone-secreting pituitary adenoma (GHSPA) [MIM:102200]; also known as familial isolated somatotropinomas (FIS) or isolated familial somatotropinoma (IFS) or familial somatotrophinoma or acromegaly due to pituitary adenoma.    Defects in AIP are a cause of ACTH-secreting pituitary adenoma (ASPA) [MIM:219090]; also known as pituitary Cushing disease. A pituary adenoma resulting in excessive production of adrenocorticotropic hormone. This leads to hypersecretion of cortisol by the adrenal glands and ACTH-dependent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and trunkal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. Defects in AIP are a cause of prolactin-secreting pituitary adenoma (PSPA) [MIM:600634]; also known as prolactinoma. Prolactin-secreting pituitary adenoma is the most common type of hormonally active pituitary adenoma.
[AIP_HUMAN] May play a positive role in AHR-mediated (aromatic hydrocarbon receptor) signaling, possibly by influencing its receptivity for ligand and/or its nuclear targeting. Cellular negative regulator of the hepatitis B virus (HBV) X protein. [HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function. 
Publication Abstract from PubMed
Mutations of the aryl hydrocarbon receptor interacting protein (AIP) have been associated with familial isolated pituitary adenomas predisposing to young-onset acromegaly and gigantism. The precise tumorigenic mechanism is not well understood as AIP interacts with a large number of independent proteins as well as three chaperone systems, HSP90, HSP70 and TOMM20. We have determined the structure of the TPR domain of AIP at high resolution, which has allowed a detailed analysis of how disease-associated mutations impact on the structural integrity of the TPR domain. A subset of C-terminal alpha-7 helix (Calpha-7h) mutations, R304* (nonsense mutation), R304Q, Q307* and R325Q, a known site for AhR and PDE4A5 client-protein interaction, occur beyond those that interact with the conserved MEEVD and EDDVE sequences of HSP90 and TOMM20. These C-terminal AIP mutations appear to only disrupt client-protein binding to the Calpha-7h, while chaperone binding remains unaffected, suggesting that failure of client-protein interaction with the Calpha-7h is sufficient to predispose to pituitary adenoma. We have also identified a molecular switch in the AIP TPR-domain that allows recognition of both the conserved HSP90 motif, MEEVD, and the equivalent sequence (EDDVE) of TOMM20.
Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal alpha-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition.,Morgan RM, Hernandez-Ramirez LC, Trivellin G, Zhou L, Roe SM, Korbonits M, Prodromou C PLoS One. 2012;7(12):e53339. doi: 10.1371/journal.pone.0053339. Epub 2012 Dec 31. PMID:23300914
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.