Structure of the TPR Domain of AIP: Lack of Client Protein Interaction with the C-Terminal α-7 Helix of the TPR Domain of AIP Is Sufficient for Pituitary Adenoma Predisposition

Abstract

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 α-7 helix (Cα-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 Cα-7h, while chaperone binding remains unaffected, suggesting that failure of client-protein interaction with the Cα-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.

Screening for AIP gene mutations in a Han Chinese pituitary adenoma cohort followed by LOH analysis

“…Of the missense variants detected here, c.733GOA (p.E245K), c.784GOA (p.D262N), c.955GOA (p.E319K), c.967COT (p.R323W), and c.976GOA (p.G326R) are located in the tetratricopeptide repeat (TPR) domain of the AIP protein, which has been recently proved to be sufficient for PA predisposition by interaction with some client proteins (11). And c.90TOG (p.D30E) and c.355COT (p.R119W) lie in the FK506-binding protein (FKBP) homology domain (Fig.…”

“…cgi?idZindex, last access: 04 May 2013) created by the Structural Bioinformatics Group, Imperial College, London (9). The AIP protein structure for prediction was based on the work by Linnert et al (10) and Morgan et al (11). The *.pdb model generated from Phyre2 was loaded and the 3D structure visualized using PyMOL Software (http://www.pymol.org/).…”

Aryl Hydrocarbon Receptor Interacting Protein Targets IRF7 to Suppress Antiviral Signaling and the Induction of Type I Interferon

“…Human AIP cDNA was PCR-amplified and cloned in pCDNA-Myc. Myc-AIP was provided by Dr. Marta Karbonits (William Harvey Research Institute) (33). AIP deletion mutants were amplified by PCR and cloned in pCDNA-Myc.…”

“…The human AIP gene encodes a 37-kDa protein of 330 amino acids. AIP contains an N-terminal immunophilin-like domain, three C-terminal tetratricopeptide repeat (TPR) domains, and an alpha-7 helix (32,33). Previous studies have established that AIP forms a tetrameric complex together with AhR and a dimer of Hsp90 in the cytoplasm (34,35).…”

AIP and the somatostatin system in pituitary tumours

“…AIP is a co-chaperone with an N-terminal immunophilin-like domain (Linnert et al 2012), which is unable to mediate immunophilin responses (Carver et al 1998, Laenger et al 2009) and a highly conserved C-terminal domain with three tetratricopeptide repeat (TPR) motifs and a C-terminal α-7 helix (Morgan et al 2012), which mediate its interactions with a number of partners (Trivellin & Korbonits 2011). According to experimental data, AIP has a long half-life of 32.7 h in humans and 30.4 h in mice, which may indicate that it is an abundant and highly structured protein (Hernández-Ramírez et al 2016).…”