Complex Regulation of Repeat Domain Proteins
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Nucleocytoplasmic Shuttling of the Glucocorticoid Receptor Is Influenced by Tetratricopeptide Repeat-Containing Proteins Gisela I
© 2020. Published by The Company of Biologists Ltd | Journal of Cell Science (2020) 133, jcs238873. doi:10.1242/jcs.238873 RESEARCH ARTICLE Nucleocytoplasmic shuttling of the glucocorticoid receptor is influenced by tetratricopeptide repeat-containing proteins Gisela I. Mazaira1,*, Pablo C. Echeverria2,* and Mario D. Galigniana1,3,‡ ABSTRACT FKBP52 (also known as FKBP4), FKBP51 (FKBP5) and CyP40 It has been demonstrated that tetratricopeptide-repeat (TPR) domain (PPID), and the immunophilin-like proteins PP5, FKBPL (WISp39) proteins regulate the subcellular localization of glucocorticoid receptor and FKBP37 (ARA9/XAP2/AIP) are counted among the best (GR). This study analyses the influence of the TPR domain of high characterized members of the TPR domain family of proteins molecular weight immunophilins in the retrograde transport and associated with nuclear receptor family members via Hsp90 (Pratt nuclear retention of GR. Overexpression of the TPR peptide et al., 2004a; Storer et al., 2011). TPR domains are composed of prevented efficient nuclear accumulation of the GR by disrupting the loosely conserved 34 amino acid sequence motifs that are found in formation of complexes with the dynein-associated immunophilin arrays comprising between 2 and 20 repeats, wherein the repeats pack FKBP52 (also known as FKBP4), the adaptor transporter importin-β1 against each other giving rise to coiled and superhelical structures (KPNB1), the nuclear pore-associated glycoprotein Nup62 and nuclear (Perez-Riba and Itzhaki, 2019). Originally identified in components of matrix-associated structures. We also show that nuclear import of GR the anaphase-promoting complex (Sikorski et al., 1991), TPR was impaired, whereas GR nuclear export was enhanced. domains are now known to mediate specific protein interactions in Interestingly, the CRM1 (exportin-1) inhibitor leptomycin-B abolished numerous cellular contexts. -
Consensus Tetratricopeptide Repeat Proteins Are Complex Superhelical 2 Nanosprings
bioRxiv preprint doi: https://doi.org/10.1101/2021.03.27.437344; this version posted August 30, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Consensus tetratricopeptide repeat proteins are complex superhelical 2 nanosprings 1, ∗ 1 1 2 2 3 Marie Synakewicz, Rohan S. Eapen, Albert Perez-Riba, Daniela Bauer, Andreas Weißl, 3 3 2 1, ∗ 4, ∗ 4 Gerhard Fischer, Marko Hyv¨onen, Matthias Rief, Laura S. Itzhaki, and Johannes Stigler 1 5 Department of Pharmacology, University of Cambridge, 6 Tennis Court Road, Cambridge, CB2 1PD, United Kingdom 2 7 Physik-Department, Technische Universit¨atM¨unchen, 8 James-Franck-Straße 1, 85748 Garching, Germany 3 9 Department of Biochemistry, University of Cambridge, 10 Tennis Court Road, Cambridge, CB2 1GA, United Kingdom 4 11 Gene Center Munich, Ludwig-Maximilians-Universit¨atM¨unchen, 12 Feodor-Lynen-Straße 25, 81377 M¨unchen,Germany 13 (Dated: August 20, 2021) Abstract. Tandem-repeat proteins comprise small secondary structure motifs that stack to form one- dimensional arrays with distinctive mechanical properties that are proposed to direct their cellular functions. Here, we use single-molecule optical tweezers to study the folding of consensus-designed tetratricopeptide repeats (CTPRs) | superhelical arrays of short helix-turn-helix motifs. We find that CTPRs display a spring-like mechanical response in which individual repeats undergo rapid equilibrium fluctuations between folded and unfolded conformations. We rationalise the force response using Ising models and dissect the folding pathway of CTPRs under mechanical load, revealing how the repeat arrays form from the centre towards both termini simultaneously. -
Small Glutamine-Rich Tetratricopeptide Repeat
www.nature.com/scientificreports OPEN Small Glutamine-Rich Tetratricopeptide Repeat- Containing Protein Alpha (SGTA) Received: 04 January 2016 Accepted: 07 June 2016 Ablation Limits Offspring Viability Published: 30 June 2016 and Growth in Mice Lisa K. Philp1, Tanya K. Day1, Miriam S. Butler1, Geraldine Laven-Law1, Shalini Jindal1, Theresa E. Hickey1, Howard I. Scher2, Lisa M. Butler1,3,* & Wayne D. Tilley1,3,* Small glutamine-rich tetratricopeptide repeat-containing protein α (SGTA) has been implicated as a co-chaperone and regulator of androgen and growth hormone receptor (AR, GHR) signalling. We investigated the functional consequences of partial and full Sgta ablation in vivo using Cre-lox Sgta- null mice. Sgta+/− breeders generated viable Sgta−/− offspring, but at less than Mendelian expectancy. Sgta−/− breeders were subfertile with small litters and higher neonatal death (P < 0.02). Body size was significantly and proportionately smaller in male and femaleSgta −/− (vs WT, Sgta+/− P < 0.001) from d19. Serum IGF-1 levels were genotype- and sex-dependent. Food intake, muscle and bone mass and adiposity were unchanged in Sgta−/−. Vital and sex organs had normal relative weight, morphology and histology, although certain androgen-sensitive measures such as penis and preputial size, and testis descent, were greater in Sgta−/−. Expression of AR and its targets remained largely unchanged, although AR localisation was genotype- and tissue-dependent. Generally expression of other TPR- containing proteins was unchanged. In conclusion, this thorough investigation of SGTA-null mutation reports a mild phenotype of reduced body size. The model’s full potential likely will be realised by genetic crosses with other models to interrogate the role of SGTA in the many diseases in which it has been implicated. -
Supplementary Table S4. FGA Co-Expressed Gene List in LUAD
Supplementary Table S4. FGA co-expressed gene list in LUAD tumors Symbol R Locus Description FGG 0.919 4q28 fibrinogen gamma chain FGL1 0.635 8p22 fibrinogen-like 1 SLC7A2 0.536 8p22 solute carrier family 7 (cationic amino acid transporter, y+ system), member 2 DUSP4 0.521 8p12-p11 dual specificity phosphatase 4 HAL 0.51 12q22-q24.1histidine ammonia-lyase PDE4D 0.499 5q12 phosphodiesterase 4D, cAMP-specific FURIN 0.497 15q26.1 furin (paired basic amino acid cleaving enzyme) CPS1 0.49 2q35 carbamoyl-phosphate synthase 1, mitochondrial TESC 0.478 12q24.22 tescalcin INHA 0.465 2q35 inhibin, alpha S100P 0.461 4p16 S100 calcium binding protein P VPS37A 0.447 8p22 vacuolar protein sorting 37 homolog A (S. cerevisiae) SLC16A14 0.447 2q36.3 solute carrier family 16, member 14 PPARGC1A 0.443 4p15.1 peroxisome proliferator-activated receptor gamma, coactivator 1 alpha SIK1 0.435 21q22.3 salt-inducible kinase 1 IRS2 0.434 13q34 insulin receptor substrate 2 RND1 0.433 12q12 Rho family GTPase 1 HGD 0.433 3q13.33 homogentisate 1,2-dioxygenase PTP4A1 0.432 6q12 protein tyrosine phosphatase type IVA, member 1 C8orf4 0.428 8p11.2 chromosome 8 open reading frame 4 DDC 0.427 7p12.2 dopa decarboxylase (aromatic L-amino acid decarboxylase) TACC2 0.427 10q26 transforming, acidic coiled-coil containing protein 2 MUC13 0.422 3q21.2 mucin 13, cell surface associated C5 0.412 9q33-q34 complement component 5 NR4A2 0.412 2q22-q23 nuclear receptor subfamily 4, group A, member 2 EYS 0.411 6q12 eyes shut homolog (Drosophila) GPX2 0.406 14q24.1 glutathione peroxidase -
Appendix 2. Significantly Differentially Regulated Genes in Term Compared with Second Trimester Amniotic Fluid Supernatant
Appendix 2. Significantly Differentially Regulated Genes in Term Compared With Second Trimester Amniotic Fluid Supernatant Fold Change in term vs second trimester Amniotic Affymetrix Duplicate Fluid Probe ID probes Symbol Entrez Gene Name 1019.9 217059_at D MUC7 mucin 7, secreted 424.5 211735_x_at D SFTPC surfactant protein C 416.2 206835_at STATH statherin 363.4 214387_x_at D SFTPC surfactant protein C 295.5 205982_x_at D SFTPC surfactant protein C 288.7 1553454_at RPTN repetin solute carrier family 34 (sodium 251.3 204124_at SLC34A2 phosphate), member 2 238.9 206786_at HTN3 histatin 3 161.5 220191_at GKN1 gastrokine 1 152.7 223678_s_at D SFTPA2 surfactant protein A2 130.9 207430_s_at D MSMB microseminoprotein, beta- 99.0 214199_at SFTPD surfactant protein D major histocompatibility complex, class II, 96.5 210982_s_at D HLA-DRA DR alpha 96.5 221133_s_at D CLDN18 claudin 18 94.4 238222_at GKN2 gastrokine 2 93.7 1557961_s_at D LOC100127983 uncharacterized LOC100127983 93.1 229584_at LRRK2 leucine-rich repeat kinase 2 HOXD cluster antisense RNA 1 (non- 88.6 242042_s_at D HOXD-AS1 protein coding) 86.0 205569_at LAMP3 lysosomal-associated membrane protein 3 85.4 232698_at BPIFB2 BPI fold containing family B, member 2 84.4 205979_at SCGB2A1 secretoglobin, family 2A, member 1 84.3 230469_at RTKN2 rhotekin 2 82.2 204130_at HSD11B2 hydroxysteroid (11-beta) dehydrogenase 2 81.9 222242_s_at KLK5 kallikrein-related peptidase 5 77.0 237281_at AKAP14 A kinase (PRKA) anchor protein 14 76.7 1553602_at MUCL1 mucin-like 1 76.3 216359_at D MUC7 mucin 7, -
Exploring the Folding Energy Landscape of a Series of Designed Consensus Tetratricopeptide Repeat Proteins
PHYSICS, BIOPHYSICS AND COMPUTATIONAL BIOLOGY BIOPHYSICS AND COMPUTATIONAL BIOLOGY Correction for ‘‘The role of fluctuations and stress on the Correction for ‘‘Exploring the folding energy landscape of a effective viscosity of cell aggregates,’’ by Philippe Marmottant, series of designed consensus tetratricopeptide repeat proteins,’’ Abbas Mgharbel, Jos Ka¨fer,Benjamin Audren, Jean-Paul Rieu, by Yalda Javadi and Ewan R. G. Main, which appeared in issue Jean-Claude Vial, Boudewijn van der Sanden, Athanasius F. M. 41, October 13, 2009, of Proc Natl Acad Sci USA (106:17383– Mare´e, Franc¸ois Graner, and He´le`ne Delanoe¨-Ayari, which 17388; first published October 1, 2009; 10.1073/pnas. appeared in issue 41, October 13, 2009, of Proc Natl Acad Sci 0907455106). USA (106:17271–17275; first published September 25, 2009; The authors note that, due to a printer’s error, some text 10.1073/pnas.0902085106). appeared incorrectly on page 17384. In the left column, the The authors note that, due to a printer’s error, the affiliation second sentence in the third full paragraph, ‘‘This yielded [D]50% for Abbas Mgharbel, Benjamin Audren, Jean-Paul Rieu, and (midpoint of unfolding) and mD-N (change in solvent-accessible ⌬ H2O ⌬ H2O He´le`ne Delanoe¨-Ayari at Universite´ de Lyon appeared incor- surface area upon protein unfolding) from which GD–N/ G03j rectly in part. The name of the authors’ laboratory, Laboratoire (free energy of unfolding in water) was calculated (Table S1),’’ Mate´riaux et Phe´nome`nes Quantiques, should instead have should instead have appeared as ‘‘This yielded [D]50% (midpoint appeared as Laboratoire de Physique de la Matie`re Condense´e of unfolding) and mD-N (change in solvent-accessible surface ⌬ H2O et Nanostructures. -
Crystal Structures of the Tetratricopeptide Repeat Domains of Kinesin Light Chains: Insight Into Cargo Recognition Mechanisms
Crystal Structures of the Tetratricopeptide Repeat Domains of Kinesin Light Chains: Insight into Cargo Recognition Mechanisms Haizhong Zhu1., Han Youl Lee2., Yufeng Tong1, Bum-Soo Hong1, Kyung-Phil Kim2, Yang Shen1, Kyung Jik Lim3, Farrell Mackenzie1, Wolfram Tempel1, Hee-Won Park1,2* 1 Structural Genomics Consortium, Toronto, Ontario, Canada, 2 Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada, 3 Philip Pocock Catholic Secondary School, Mississauga, Ontario, Canada Abstract Kinesin-1 transports various cargos along the axon by interacting with the cargos through its light chain subunit. Kinesin light chains (KLC) utilize its tetratricopeptide repeat (TPR) domain to interact with over 10 different cargos. Despite a high sequence identity between their TPR domains (87%), KLC1 and KLC2 isoforms exhibit differential binding properties towards some cargos. We determined the structures of human KLC1 and KLC2 tetratricopeptide repeat (TPR) domains using X-ray crystallography and investigated the different mechanisms by which KLCs interact with their cargos. Using isothermal titration calorimetry, we attributed the specific interaction between KLC1 and JNK-interacting protein 1 (JIP1) cargo to residue N343 in the fourth TRP repeat. Structurally, the N343 residue is adjacent to other asparagines and lysines, creating a positively charged polar patch within the groove of the TPR domain. Whereas, KLC2 with the corresponding residue S328 did not interact with JIP1. Based on these finding, we propose that N343 of KLC1 can form ‘‘a carboxylate clamp’’ with its neighboring asparagine to interact with JIP1, similar to that of HSP70/HSP90 organizing protein-1’s (HOP1) interaction with heat shock proteins. For the binding of cargos shared by KLC1 and KLC2, we propose a different site located within the groove but not involving N343. -
Intrinsic Disorder in Tetratricopeptide Repeat Proteins
International Journal of Molecular Sciences Article Intrinsic Disorder in Tetratricopeptide Repeat Proteins 1, 1, 1, 2 Nathan W. Van Bibber y, Cornelia Haerle y, Roy Khalife y, Bin Xue and Vladimir N. Uversky 1,3,4,* 1 Department of Molecular Medicine Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA; [email protected] (N.W.V.B.); [email protected] (C.H.); [email protected] (R.K.) 2 Department of Cell Biology, Microbiology and Molecular Biology, School of Natural Sciences and Mathematics, College of Arts and Sciences, University of South Florida, Tampa, FL 33620, USA; [email protected] 3 USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA 4 Institute for Biological Instrumentation, Russian Academy of Sciences, Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, 4 Institutskaya St., Pushchino, 142290 Moscow Region, Russia * Correspondence: [email protected]; Tel.: +1-813-974-5816; Fax: +1-813-974-7357 These authors contributed equally to this work. y Received: 21 April 2020; Accepted: 22 May 2020; Published: 25 May 2020 Abstract: Among the realm of repeat containing proteins that commonly serve as “scaffolds” promoting protein-protein interactions, there is a family of proteins containing between 2 and 20 tetratricopeptide repeats (TPRs), which are functional motifs consisting of 34 amino acids. The most distinguishing feature of TPR domains is their ability to stack continuously one upon the other, with these stacked repeats being able to affect interaction with binding partners either sequentially or in combination. -
TITLE PAGE Exome Sequencing Identifies Variants in FKBP4 That Are
TITLE PAGE Exome sequencing identifies variants in FKBP4 that are associated with recurrent fetal loss in humans Authors: Charalambos Demetriou1*, Estelle Chanudet2, GOSgene2, Agnel Joseph3, Maya Topf3, Anna C. Thomas1, Maria Bitner-Glindzicz1, Lesley Regan4, Philip Stanier1, Gudrun E. Moore1 Affiliations: 1Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London, UK. 2Centre for Translational Omics - GOSgene, UCL Great Ormond Street Institute of Child Health, University College London, London, UK. 3Institute of Structural and Molecular Biology, Birkbeck College, London, UK. 4Department of Obstetrics and Gynaecology, St. Mary's Campus, Imperial College London, London, UK. Philip Stanier and Gudrun Moore contributed equally. *Corresponding author: Charalambos Demetriou Address: UCL Great Ormond Street Institute of Child Health 30 Guilford Street, Lonodn, WC1N 1EH Tel: 0044796 081 3545 Fax: 0044207 905 2832 Email address: [email protected] 1 ABSTRACT Recurrent pregnancy loss (RPL) is defined as two or more consecutive miscarriages and affects an estimated 1.5% of couples trying to conceive. RPL has been attributed to genetic, endocrine, immune and thrombophilic disorders, But many cases remain unexplained. We investigated a Bangladeshi family where the proband experienced 29 consecutive pregnancy losses with no successful pregnancies from three different marriages. Whole exome sequencing identified rare genetic variants in several candidate genes. These were further investigated in Asian and White European RPL cohorts, and in Bangladeshi controls. FKBP4, encoding the immunophilin FK506 binding protein 4, was identified as a plausible candidate, with three further novel variants identified in Asian patients. None were found in European patients or controls. -
Attpr10 Containing Multiple ANK and TPR Domains Exhibits Chaperone Activity and Heat-Shock Dependent Structural Switching
applied sciences Article AtTPR10 Containing Multiple ANK and TPR Domains Exhibits Chaperone Activity and Heat-Shock Dependent Structural Switching Seol Ki Paeng, Chang Ho Kang, Yong Hun Chi, Ho Byoung Chae, Eun Seon Lee, Joung Hun Park, Seong Dong Wi, Su Bin Bae, Kieu Anh Thi Phan and Sang Yeol Lee * Division of Applied Life Science (BK21+) and Plant Molecular Biotechnology Research Center, Gyeongsang National University, Jinju 52828, Korea; [email protected] (S.K.P.); [email protected] (C.H.K.); [email protected] (Y.H.C.); [email protected] (H.B.C.); [email protected] (E.S.L.); [email protected] (J.H.P.); [email protected] (S.D.W.); dnfl[email protected] (S.B.B.); [email protected] (K.A.T.P.) * Correspondence: [email protected]; Tel.: +82-55-772-1351 Received: 13 January 2020; Accepted: 10 February 2020; Published: 13 February 2020 Abstract: Among the several tetratricopeptide (TPR) repeat-containing proteins encoded by the Arabidopsis thaliana genome, AtTPR10 exhibits an atypical structure with three TPR domain repeats at the C-terminus in addition to seven ankyrin (ANK) domain repeats at the N-terminus. However, the function of AtTPR10 remains elusive. Here, we investigated the biochemical function of AtTPR10. Bioinformatic analysis revealed that AtTPR10 expression is highly enhanced by heat shock compared with the other abiotic stresses, suggesting that AtTPR10 functions as a molecular chaperone to protect intracellular proteins from thermal stresses. Under the heat shock treatment, the chaperone activity of AtTPR10 increased significantly; this was accompanied by a structural switch from the low molecular weight (LMW) protein to a high molecular weight (HMW) complex. -
FKBP4 Integrates FKBP4/Hsp90/IKK with FKBP4/Hsp70/Rela Complex To
Zong et al. Cell Death and Disease (2021) 12:602 https://doi.org/10.1038/s41419-021-03857-8 Cell Death & Disease ARTICLE Open Access FKBP4 integrates FKBP4/Hsp90/IKK with FKBP4/ Hsp70/RelA complex to promote lung adenocarcinoma progression via IKK/NF-κB signaling Shuai Zong1, Yulian Jiao1,XinLiu1,WenliMu1, Xiaotian Yuan1,YunyunQu1,2,YuXia1,ShuangLiu1,HuanxinSun1, Laicheng Wang1,BinCui1,XiaowenLiu1,PingLi3 and Yueran Zhao 1,4,5 Abstract FKBP4 belongs to the family of immunophilins, which serve as a regulator for steroid receptor activity. Thus, FKBP4 has been recognized to play a critical role in several hormone-dependent cancers, including breast and prostate cancer. However, there is still no research to address the role of FKBP4 on lung adenocarcinoma (LUAD) progression. We found that FKBP4 expression was elevated in LUAD samples and predicted significantly shorter overall survival based on TCGA and our cohort of LUAD patients. Furthermore, FKBP4 robustly increased the proliferation, metastasis, and invasion of LUAD in vitro and vivo. Mechanistic studies revealed the interaction between FKBP4 and IKK kinase complex. We found that FKBP4 potentiated IKK kinase activity by interacting with Hsp90 and IKK subunits and promoting Hsp90/IKK association. Also, FKBP4 promotes the binding of IKKγ to IKKβ, which supported the facilitation role in IKK complex assembly. We further identified that FKBP4 TPR domains are essential for FKBP4/IKK interaction 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; since its association with Hsp90 is required. In addition, FKBP4 PPIase domains are involved in FKBP4/IKKγ interaction. Interestingly, the association between FKBP4 and Hsp70/RelA favors the transport of RelA toward the nucleus. -
'Design of Armadillo Repeat Protein Scaffolds'
Zurich Open Repository and Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2008 Design of armadillo repeat protein scaffolds Parmeggiani, F Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-4818 Dissertation Published Version Originally published at: Parmeggiani, F. Design of armadillo repeat protein scaffolds. 2008, University of Zurich, Faculty of Medicine. Design of Armadillo Repeat Protein Scaffolds Dissertation zur Erlangung der naturwissenschaftlichen Doktorwürde (Dr. sc. nat.) vorgelegt der Mathematisch-naturwissenschaftlichen Fakultät der Universität Zürich von Fabio Parmeggiani aus Italien Promotionskomitee Prof. Dr. Andreas Plückthun (Leitung der Dissertation) Prof. Dr. Markus Grütter Prof. Dr. Donald Hilvert Zürich, 2008 To my grandfather, who showed me the essence of curiosity “It is easy to add more of the same to old knowledge, but it is difficult to explain the new” Benno Müller-Hill Table of Contents 1 Table of contents Summary 3 Chapter 1: Peptide binders 7 Part I: Peptide binders 8 Modular interaction domains as natural peptide binders 9 SH2 domains 10 PTB domains 10 PDZ domains 12 14-3-3 domains 12 SH3 domains 12 WW domains 12 Peptide recognition by major histocompatibility complexes 13 Repeat proteins targeting peptides 15 Armadillo repeat proteins 16 Tetratricopeptide repeat proteins (TPR) 16 Beta propellers 16 Peptide binding by antibodies 18 Alternative scaffolds: a new approach to peptide binding 20 Part