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Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations.

Kjaer S, Hanrahan S, Totty N, McDonald NQ
Nat Struct Mol Biol 17 726-31 (2010)
Cited: 39 times
EuropePMC logo PMID: 20473317

Abstract

The maturation of human RET is adversely affected by a range of missense mutations found in patients with Hirschsprung's disease (HSCR), a complex multigenic disease. Here we show that two N-terminal cadherin-like domains, CLD1 and CLD2 (CLD(1-2)), from human RET adopt a clam-shell arrangement distinct from that of classical cadherins. CLD1 structural elements and disulfide composition are unique to mammals, indicating an unexpected structural diversity within higher and lower vertebrate RET CLD regions. We identify two unpaired cysteines that predispose human RET to maturation impediments in the endoplasmic reticulum and establish a quantitative cell-based RET maturation assay that offers a biochemical correlate of HSCR disease severity. Our findings provide a key conceptual framework and means of testing and predicting genotype-phenotype correlations in HSCR.

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  1. Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors. Cai K, Zhang X, Bai XC. Chem Rev 122 13952-13988 (2022)

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  4. The dipeptidyl peptidase IV inhibitors vildagliptin and K-579 inhibit a phospholipase C: a case of promiscuous scaffolds in proteins. Chakraborty S, Rendón-Ramírez A, Ásgeirsson B, Dutta M, Ghosh AS, Oda M, Venkatramani R, Rao BJ, Dandekar AM, Goñi FM. F1000Res 2 286 (2013)
  5. A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing. Adams SE, Purkiss AG, Knowles PP, Nans A, Briggs DC, Borg A, Earl CP, Goodman KM, Nawrotek A, Borg AJ, McIntosh PB, Houghton FM, Kjær S, McDonald NQ. Structure 29 694-708.e7 (2021)
  6. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC. Elife 8 (2019)
  7. Cryo-EM structure of the activated RET signaling complex reveals the importance of its cysteine-rich domain. Bigalke JM, Aibara S, Roth R, Dahl G, Gordon E, Dorbéus S, Amunts A, Sandmark J. Sci Adv 5 eaau4202 (2019)


Reviews citing this publication (10)

  1. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Guerriero CJ, Brodsky JL. Physiol. Rev. 92 537-576 (2012)
  2. RET revisited: expanding the oncogenic portfolio. Mulligan LM. Nat. Rev. Cancer 14 173-186 (2014)
  3. Structure and physiology of the RET receptor tyrosine kinase. Ibáñez CF. Cold Spring Harb Perspect Biol 5 (2013)
  4. Structural studies of GDNF family ligands with their receptors-Insights into ligand recognition and activation of receptor tyrosine kinase RET. Wang X. Biochim. Biophys. Acta 1834 2205-2212 (2013)
  5. Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases. Needham PG, Guerriero CJ, Brodsky JL. Cold Spring Harb Perspect Biol 11 (2019)
  6. Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. Wagner SM, Zhu S, Nicolescu AC, Mulligan LM. Clinics (Sao Paulo) 67 Suppl 1 77-84 (2012)
  7. Structure and function of RET in multiple endocrine neoplasia type 2. Plaza-Menacho I. Endocr. Relat. Cancer 25 T79-T90 (2018)
  8. Multiple Endocrine Neoplasia Syndromes from Genetic and Epigenetic Perspectives. Khatami F, Tavangar SM. Biomark Insights 13 1177271918785129 (2018)
  9. The RET gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and RET mutation results in Hirschsprung's disease. Bhattarai C, Poudel PP, Ghosh A, Kalthur SG. AIMS Neurosci 9 128-149 (2022)
  10. The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers. Li Q, Cao Z, Zhao S. Int J Med Sci 19 659-668 (2022)

Articles citing this publication (21)

  1. Mutations in the NRG1 gene are associated with Hirschsprung disease. Tang CS, Ngan ES, Tang WK, So MT, Cheng G, Miao XP, Leon TY, Leung BM, Hui KJ, Lui VH, Chen Y, Chan IH, Chung PH, Liu XL, Wong KK, Sham PC, Cherny SS, Tam PK, Garcia-Barcelo MM. Hum. Genet. 131 67-76 (2012)
  2. RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Goodman KM, Kjær S, Beuron F, Knowles PP, Nawrotek A, Burns EM, Purkiss AG, George R, Santoro M, Morris EP, McDonald NQ. Cell Rep 8 1894-1904 (2014)
  3. Potential use of skin-derived precursors (SKPs) in establishing a cell-based treatment model for Hirschsprung's disease. Kwok CK, Tam PK, Ngan ES. J. Pediatr. Surg. 48 619-628 (2013)
  4. Multiple functional effects of RET kinase domain sequence variants in Hirschsprung disease. Hyndman BD, Gujral TS, Krieger JR, Cockburn JG, Mulligan LM. Hum. Mutat. 34 132-142 (2013)
  5. Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). Kosfeld A, Kreuzer M, Daniel C, Brand F, Schäfer AK, Chadt A, Weiss AC, Riehmer V, Jeanpierre C, Klintschar M, Bräsen JH, Amann K, Pape L, Kispert A, Al-Hasani H, Haffner D, Weber RG. Hum. Genet. 135 69-87 (2016)
  6. Fragment-Based Discovery of a Dual pan-RET/VEGFR2 Kinase Inhibitor Optimized for Single-Agent Polypharmacology. Frett B, Carlomagno F, Moccia ML, Brescia A, Federico G, De Falco V, Admire B, Chen Z, Qi W, Santoro M, Li HY. Angew. Chem. Int. Ed. Engl. 54 8717-8721 (2015)
  7. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. J. Biol. Chem. 286 14628-14638 (2011)
  8. Narcolepsy after A/H1N1 vaccination. Mendes MF, Valladares Neto Dde C, Azevedo RA, Caramelli P. Clinics (Sao Paulo) 67 77-78 (2012)
  9. Exon Skipping in the RET Gene Encodes Novel Isoforms That Differentially Regulate RET Protein Signal Transduction. Gabreski NA, Vaghasia JK, Novakova SS, McDonald NQ, Pierchala BA. J. Biol. Chem. 291 16249-16262 (2016)
  10. Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients. Jóri B, Kamps R, Xanthoulea S, Delvoux B, Blok MJ, Van de Vijver KK, de Koning B, Oei FT, Tops CM, Speel EJ, Kruitwagen RF, Gomez-Garcia EB, Romano A. Oncotarget 6 41108-41122 (2015)
  11. Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. Jannot AS, Amiel J, Pelet A, Lantieri F, Fernandez RM, Verheij JB, Garcia-Barcelo M, Arnold S, Ceccherini I, Borrego S, Hofstra RM, Tam PK, Munnich A, Chakravarti A, Clerget-Darpoux F, Lyonnet S. Eur. J. Hum. Genet. 20 917-920 (2012)
  12. Defects in the calcium-binding region drastically affect the cadherin-like domains of RET tyrosine kinase. Gao C, Grøtli M, Eriksson LA. Phys Chem Chem Phys 18 8673-8681 (2016)
  13. Functional analyses of RET mutations in Chinese Hirschsprung disease patients. Leon TY, So MT, Lui VC, Hofstra RM, Tam PK, Ngan ES, Garcia-Barceló MM. Birth Defects Res. Part A Clin. Mol. Teratol. 94 47-51 (2012)
  14. Structure and biophysical characterization of the human full-length neurturin-GFRa2 complex: A role for heparan sulfate in signaling. Sandmark J, Dahl G, Öster L, Xu B, Johansson P, Akerud T, Aagaard A, Davidsson P, Bigalke JM, Winzell MS, Rainey GJ, Roth RG. J. Biol. Chem. 293 5492-5508 (2018)
  15. Zebrafish GDNF and its co-receptor GFRα1 activate the human RET receptor and promote the survival of dopaminergic neurons in vitro. Saarenpää T, Kogan K, Sidorova Y, Mahato AK, Tascón I, Kaljunen H, Yu L, Kallijärvi J, Jurvansuu J, Saarma M, Goldman A. PLoS ONE 12 e0176166 (2017)
  16. Binding of EphrinA5 to RET receptor tyrosine kinase: An in vitro study. Liu Y, Kaljunen H, Pavić A, Saarenpää T, Himanen JP, Nikolov DB, Goldman A. PLoS ONE 13 e0198291 (2018)
  17. Downregulation of Protein Tyrosine Phosphatase Receptor Type R Accounts for the Progression of Hirschsprung Disease. Tian J, Zeng C, Tian Z, Lin Y, Wang B, Pan Y, Shu Z, Jiang X. Front Mol Neurosci 12 92 (2019)
  18. Germline RET Leu56Met Variant Is Likely Not Causative of Multiple Endocrine Neoplasia Type 2. Hansen AR, Borgwardt L, Rasmussen ÅK, Godballe C, Poulsen MM, Vieira FG, Mathiesen JS, Rossing M. Front Endocrinol (Lausanne) 12 764512 (2021)
  19. MiR-195-5p inhibits proliferation and invasion of nerve cells in Hirschsprung disease by targeting GFRA4. Wang G, Wang H, Zhang L, Guo F, Wu X, Liu Y. Mol Cell Biochem (2021)
  20. RET enhancer haplotype-dependent remodeling of the human fetal gut development program. Chatterjee S, Fries LE, Yaacov O, Hu N, Berk-Rauch HE, Chakravarti A. PLoS Genet 19 e1011030 (2023)
  21. Unexpected structures formed by the kinase RET C634R mutant extracellular domain suggest potential oncogenic mechanisms in MEN2A. Liu Y, De Castro Ribeiro O, Haapanen O, Craven GB, Sharma V, Muench SP, Goldman A. J Biol Chem 298 102380 (2022)


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