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.
Highlights
Mutations in aryl hydrocarbon receptor interacting protein (AIP) [1,2] have been linked to familial isolated pituitary adenomas (FIPA) [3,4,5], a condition most often characterized by young-onset growth hormone and prolactin-secreting pituitary tumors, which leads to acromegaly and gigantism
We found that the EDASRMEEVD (HSP90) and AQSLAEDDVE (TOMM20) peptides bind within the tetratricopeptide repeat (TPR)-domain cleft and adopt a similar backbone conformation (Fig. 1)
The structures show that the C-terminal carboxylate group and the C-terminal aspartate (HSP90) or glutamate (TOMM20) side-chain are involved in a series of hydrogen bonds that is reminiscent of the carboxylate clamp seen in the MEEVDHOP complex [11] (Fig. 4)
Summary
Mutations in aryl hydrocarbon receptor interacting protein (AIP) [1,2] have been linked to familial isolated pituitary adenomas (FIPA) [3,4,5], a condition most often characterized by young-onset growth hormone and prolactin-secreting pituitary tumors (reviewed by [6]), which leads to acromegaly and gigantism. The human AIP gene encodes a 37 kDa protein of 330 amino acids that, based on similarities to other proteins, is predicted to have an N-terminal immunophilin-like domain [7] and a C-terminal tetratricopeptide repeat (TPR) domain. The TPR domain of AIP appears to be similar to the corresponding domains of HOP, CHIP, CYP40, PP5, FKBP51 and FKBP52 and the aryl hydrocarbon receptor-interacting protein like 1 (AIPL1) (Fig. 1A). TOMM20 acts as a receptor for unfolded proteins destined for translocation across the outer mitochondrial membrane [19]. Together, these chaperones are responsible for the activation and maturation of a vast array of other proteins
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
