journal.pone.0053339.pdf (1.75 MB)
Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal a-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition
journal contribution
posted on 2023-06-08, 14:12 authored by Rhodri M L Morgan, Laura C Hernández-Ramírez, Giampaolo Trivellin, Lihong Zhou, S. Mark Roe, Márta Korbonits, Chrisostomos ProdromouChrisostomos ProdromouMutations 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 a-7 helix (Ca-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 Ca-7h, while chaperone binding remains unaffected, suggesting that failure of client-protein interaction with the Ca-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.
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- Published
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- Published version
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PLoS ONEISSN
1932-6203Publisher
Public Library of ScienceExternal DOI
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12Volume
7Article number
e53339Department affiliated with
- Biochemistry Publications
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- Yes
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- Yes
Legacy Posted Date
2013-01-29First Open Access (FOA) Date
2017-10-31First Compliant Deposit (FCD) Date
2017-10-31Usage metrics
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