Role of the nucleotidyl cyclase helical domain in catalytically active dimer formation

Proceedings of the National Academy of Sciences of the United States of America
Irene VercellinoVolodymyr M Korkhov

Abstract

Nucleotidyl cyclases, including membrane-integral and soluble adenylyl and guanylyl cyclases, are central components in a wide range of signaling pathways. These proteins are architecturally diverse, yet many of them share a conserved feature, a helical region that precedes the catalytic cyclase domain. The role of this region in cyclase dimerization has been a subject of debate. Although mutations within this region in various cyclases have been linked to genetic diseases, the molecular details of their effects on the enzymes remain unknown. Here, we report an X-ray structure of the cytosolic portion of the membrane-integral adenylyl cyclase Cya from Mycobacterium intracellulare in a nucleotide-bound state. The helical domains of each Cya monomer form a tight hairpin, bringing the two catalytic domains into an active dimerized state. Mutations in the helical domain of Cya mimic the disease-related mutations in human proteins, recapitulating the profiles of the corresponding mutated enzymes, adenylyl cyclase-5 and retinal guanylyl cyclase-1. Our experiments with full-length Cya and its cytosolic domain link the mutations to protein stability, and the ability to induce an active dimeric conformation of the catalytic domains. Seq...Continue Reading

References

May 15, 1990·Analytical Biochemistry·R Alvarez, D V Daniels
Jun 25, 1996·Proceedings of the National Academy of Sciences of the United States of America·R E WhisnantC W Dessauer
Jul 31, 1999·Science·J J TesmerS R Sprang
Nov 23, 2000·Biochemistry·J J TesmerS R Sprang
Jan 29, 2005·The EMBO Journal·Sangita C SinhaJürgen U Linder
Mar 17, 2005·Frontiers in Bioscience : a Journal and Virtual Library·Lincoln Ross Potter
Aug 29, 2006·Journal of Molecular Biology·Margarita KamenetskyClemens Steegborn
Jan 24, 2007·Reviews of Physiology, Biochemistry and Pharmacology·S C Sinha, S R Sprang
May 20, 2008·Investigative Ophthalmology & Visual Science·Veronique B D KitiratschkySusanne Kohl
Apr 2, 2009·Nature Reviews. Drug Discovery·Sandra PierreKlaus Scholich
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Wolfgang Kabsch
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Dec 1, 2010·Physical Chemistry Chemical Physics : PCCP·Yevhen PolyhachGunnar Jeschke
May 20, 2011·Nucleic Acids Research·Robert D FinnSean R Eddy
Mar 13, 2012·Annual Review of Biochemistry·Emily R Derbyshire, Michael A Marletta
Apr 17, 2012·Acta Crystallographica. Section D, Biological Crystallography·Oliver S SmartGérard Bricogne
Dec 25, 2012·BMC Bioinformatics·Jose M DuarteGuido Capitani
Dec 24, 2013·The Journal of Biological Chemistry·Benesh JosephEnrica Bordignon
Feb 12, 2014·Proceedings of the National Academy of Sciences of the United States of America·Melody G CampbellMichael A Marletta
Feb 25, 2014·Structure·Eric S UnderbakkeMichael A Marletta
Feb 26, 2014·Proceedings of the National Academy of Sciences of the United States of America·Silke KleinboeltingClemens Steegborn
Apr 5, 2014·Annals of Neurology·Ying-Zhang ChenAli Torkamani
Oct 9, 2014·IUCrJ·Deivanayaga BarathyKaza Suguna
Apr 12, 2016·Movement Disorders : Official Journal of the Movement Disorder Society·Florence C F ChangVictor S C Fung
Jun 2, 2016·Proceedings of the National Academy of Sciences of the United States of America·Mio OhkiSam-Yong Park
Jun 9, 2016·Nature Structural & Molecular Biology·Kaspar P Locher
Oct 21, 2016·The FEBS Journal·Nikhil G BharambeKaza Suguna

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Citations

Jan 26, 2018·Journal of Cardiovascular Development and Disease·Tanya A Baldwin, Carmen W Dessauer
Aug 15, 2019·Protein Science : a Publication of the Protein Society·Andrzej WeichselWilliam R Montfort
Dec 7, 2019·The FEBS Journal·Agata ButrynAllen M Orville
Jun 13, 2020·Scientific Reports·Rana Rehan KhalidMichael Kokkinidis
Apr 20, 2018·Emerging Topics in Life Sciences·Gunnar Jeschke
Feb 28, 2020·Cellular Signalling·Ferenc A Antoni
Apr 29, 2021·Cell Reports·Roberto Vazquez NunezStephan Gruber
Mar 22, 2021·Cellular and Molecular Gastroenterology and Hepatology·Hari Prasad, Sandhya S Visweswariah
Jul 16, 2021·Journal of Photochemistry and Photobiology. B, Biology·Misato IkomaMasahide Terazima

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Methods Mentioned

BETA
X-ray
size exclusion chromatography
circular dichroism

Software Mentioned

Eppic
Cya
HMMER
Cya SOL
XDS
SAD
DEER
MR
Phenix
MANT

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