PMCID: PMC3534021This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

A Laenger

A Puga

A Raitila

AF Daly

AJ Perry

AP Heaney

B Bukau

B Panaretou

BD Hollingshead

C Prodromou

C Scheufler

CA Leontiou

Chrisostomos Prodromou

CM Greiser

D Spengler

DR Bell

E Heliovaara

EB Krissinel

F Glaser

G Huang

G Siligardi

G Trivellin

GB Bolger

Giampaolo Trivellin

Giorgio Colombo

H Ashkenazy

HS Chahal

HS Feigelson

I Persson

IW Davis

JL Marlowe

LA Carver

Laura C. Hernández-Ramírez

LH Pearl

Lihong Zhou

M Fujimoto

M Landau

M Linnert

M Yano

M Zhang

MP Mayer

Márta Korbonits

N Kuzhandaivelu

O Vierimaa

P Emsley

P Pocar

PH Pang

PV Afonine

Q Zeng

Rhodri M. L. Morgan

S Igreja

S Safe

S. Mark Roe

SK de Oliveira

SK Kolluri

W Cai

Z Ozfirat

PLoS ONE

English

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 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

Rhodri M L Morgan (16156640)

Laura C Hernández-Ramírez (16156643)

Giampaolo Trivellin (106006)

Lihong Zhou (106007)

S. Mark Roe (22167)

Márta Korbonits (59514)

Chrisostomos Prodromou (4463035)

Sussex Research Online

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

Morgan, RML

Hernandez-Ramirez, LC

Trivellin, G

Zhou, L

Roe, SM

Korbonits, M

Prodromou, C

Queen Mary Research Online

Activation of the ATPase activity of hsp90 by the stress-regulated cochaperone aha1.

AIP and its interacting partners.

AIP gene and familial isolated pituitary adenomas.

AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins.

AIP mutation in pituitary adenomas in the 18th century and today.

Aromatic hydrocarbon receptor interaction with the retinoblastoma protein potentiates repression of E2F-dependent transcription and cell cycle arrest.

Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families.

Attenuation of the activity of the cAMP-specific phosphodiesterase PDE4A5 by interaction with the immunophilin XAP2.

Chaperoned ubiquitylation–crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex.

Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families.

Characterization of the Ah receptor-associated protein,

Clinical characteristics and therapeutic responses in patients with germline AIP mutations and pituitary adenomas: an international collaborative study.

Clinical, genetic and molecular characterization of patients with familial isolated pituitary adenomas (FIPA).

Co-chaperone regulation of conformational switching in the Hsp90 ATPase cycle.

ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures.

ConSurf 2010: calculating evolutionary conservation in sequence and structure of proteins and nucleic acids.

ConSurf: identification of functional regions in proteins by surface-mapping of phylogenetic information.

Coot: model-building tools for molecular graphics.

determine cellular protein folding/degradation balances.

Early involvement of estrogen-induced pituitary tumor transforming gene and fibroblast growth factor expression in prolactinoma pathogenesis.

Elferink CJ (2005) Multiple mechanisms are involved in Ah receptormediated cell cycle arrest.

Estrogens and breast cancer.

Horwich A

Hsp70 chaperones: cellular functions and molecular mechanism. Cellular and molecular life sciences :

Hsp90: Structure and Function. Topics in current chemistry.

Ligand-dependent interaction of the aryl hydrocarbon receptor with a novel immunophilin homolog in vivo.

Mechanisms of inhibitory aryl hydrocarbon receptor-estrogen receptor crosstalk in human breast cancer cells.

Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis.

Mice with inactivation of aryl hydrocarbon receptor-interacting protein (Aip) display complete penetrance of pituitary adenomas with aberrant ARNT expression.

Molecular interactions of the aryl hydrocarbon receptor and its biological and toxicological relevance for reproduction.

Molecular mechanisms of p21 and p27 induction by 3-methylcholanthrene, an arylhydrocarbon receptor agonist, involved in antiproliferation of human umbilical vascular endothelial cells.

MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.

NMR assignments of the FKBP-type PPIase domain of the human aryl-hydrocarbon receptor-interacting protein (AIP).

p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells.

Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor.

Pituitary adenoma predisposition caused by germline mutations in the AIP gene.

Poland A

Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain.

Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones.

Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement.

Smolenski A

Structure of TPR domain-peptide complexes: critical elements in the assembly of the Hsp70-Hsp90 multichaperone machine.

Structure, topology and function of the translocase of the outer membrane of mitochondria. Plant physiology and biochemistry : PPB/Societe francaise de physiologie vegetale 46:

Studies on estrogen induced pituitary tumor in the rat with special reference to the relationship of the tuberoinfundibular dopamine neuron system.

Tau Triage Decisions Mediated by the Chaperone Network.

The ’active life’ of Hsp90 complexes.

The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function.

The contributions of oestrogen receptor isoforms to the development of papillary and anaplastic thyroid carcinomas.

The expression of AIP-related molecules in elucidation of cellular pathways in pituitary adenomas.

The Hsp90 molecular chaperone: an open and shut case for treatment.

The immunophilin-like protein XAP2 is a negative regulator of estrogen signaling through interaction with estrogen receptor alpha.

The new CCP4 Coordinate Library as a toolkit for the design of coordinate-related applications in protein crystallography.

The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas.

Towards automated crystallographic structure refinement with phenix.-refine.

XAP2 inhibits glucocorticoid receptor activity in mammalian cells.

XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation.

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

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

Rhodri M L Morgan

Laura C Hernández-Ramírez

S Mark Roe

Directory of Open Access Journals

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.

Morgan Rhodri M. L.

Hernández-Ramírez Laura C.

Trivellin Giampaolo

Zhou Lihong

Roe S. Mark

Korbonits Márta

Prodromou Chrisostomos

Public Library of Science (PLOS)

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

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 th

Laura C. Hernández-ramı́rez

CiteSeerX

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

https://figshare.com/articles/Structure_of_the_TPR_Domain_of_AIP_Lack_of_Client_Protein_Interaction_with_the_C_Terminal_7_Helix_of_the_TPR_Domain_of_AIP_Is_Sufficient_for_Pituitary_Adenoma_Predisposition__/115026

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

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Directory of Open Access Journals

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Public Library of Science (PLOS)

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