University of Sussex
Browse
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

Download (1.75 MB)
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 Prodromou
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 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

PLoS ONE

ISSN

1932-6203

Publisher

Public Library of Science

Issue

12

Volume

7

Article number

e53339

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2013-01-29

First Open Access (FOA) Date

2017-10-31

First Compliant Deposit (FCD) Date

2017-10-31

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC