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Solution structure of the pro-hormone convertase 1 pro-domain from Mus musculus.

Tangrea MA, Bryan PN, Sari N, Orban J
J Mol Biol 320 801-12 (2002)
Cited: 31 times
EuropePMC logo PMID: 12095256

Abstract

The solution structure of the mouse pro-hormone convertase (PC) 1 pro-domain was determined using heteronuclear NMR spectroscopy and is the first structure to be obtained for any of the domains in the convertase family. The ensemble of NMR-derived structures shows a well-ordered core consisting of a four-stranded antiparallel beta-sheet with two alpha-helices packed against one side of this sheet. Sequence homology suggests that the other eukaryotic PC pro-domains will have the same overall fold and most of the residues forming the hydrophobic core of PC1 are highly conserved within the PC family. However, some of the core residues are predicted by homology to be replaced by polar amino acid residues in other PC pro-domains and this may help to explain their marginal stability. Interestingly, the folding topology observed here is also seen for the pro-domain of bacterial subtilisin despite little or no sequence homology. Both the prokaryotic and eukaryotic structures have hydrophobic residues clustered on the solvent-accessible surface of their beta-sheets although the individual residue types differ. In the bacterial case this region is buried at the binding interface with the catalytic domain and, in the eukaryotic PC family, these surface residues are conserved. We therefore propose that the hydrophobic patch in the PC1 pro-domain is involved in the binding interface with its cognate catalytic domain in a similar manner to that seen for the bacterial system. The PC1 pro-domain structure also reveals potential mechanisms for the acid-induced dissociation of the complex between pro- and catalytic domains.

Reviews - 1kn6 mentioned but not cited (1)

  1. Insights from bacterial subtilases into the mechanisms of intramolecular chaperone-mediated activation of furin. Shinde U, Thomas G. Methods Mol Biol 768 59-106 (2011)

Articles - 1kn6 mentioned but not cited (5)

  1. Identification of a pH sensor in the furin propeptide that regulates enzyme activation. Feliciangeli SF, Thomas L, Scott GK, Subbian E, Hung CH, Molloy SS, Jean F, Shinde U, Thomas G. J Biol Chem 281 16108-16116 (2006)
  2. Autocatalytic activation of the furin zymogen requires removal of the emerging enzyme's N-terminus from the active site. Gawlik K, Shiryaev SA, Zhu W, Motamedchaboki K, Desjardins R, Day R, Remacle AG, Stec B, Strongin AY. PLoS One 4 e5031 (2009)
  3. Propeptides are sufficient to regulate organelle-specific pH-dependent activation of furin and proprotein convertase 1/3. Dillon SL, Williamson DM, Elferich J, Radler D, Joshi R, Thomas G, Shinde U. J Mol Biol 423 47-62 (2012)
  4. The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin. Williamson DM, Elferich J, Ramakrishnan P, Thomas G, Shinde U. J Biol Chem 288 19154-19165 (2013)
  5. Mechanism of Fine-tuning pH Sensors in Proprotein Convertases: IDENTIFICATION OF A pH-SENSING HISTIDINE PAIR IN THE PROPEPTIDE OF PROPROTEIN CONVERTASE 1/3. Williamson DM, Elferich J, Shinde U. J Biol Chem 290 23214-23225 (2015)


Reviews citing this publication (3)

  1. Cutting back on pro-protein convertases: the latest approaches to pharmacological inhibition. Fugère M, Day R. Trends Pharmacol Sci 26 294-301 (2005)
  2. PCSK1 Mutations and Human Endocrinopathies: From Obesity to Gastrointestinal Disorders. Stijnen P, Ramos-Molina B, O'Rahilly S, Creemers JW. Endocr Rev 37 347-371 (2016)
  3. Novel proteomic approaches for tissue analysis. Tangrea MA, Wallis BS, Gillespie JW, Gannot G, Emmert-Buck MR, Chuaqui RF. Expert Rev Proteomics 1 185-192 (2004)

Articles citing this publication (22)

  1. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Cunningham D, Danley DE, Geoghegan KF, Griffor MC, Hawkins JL, Subashi TA, Varghese AH, Ammirati MJ, Culp JS, Hoth LR, Mansour MN, McGrath KM, Seddon AP, Shenolikar S, Stutzman-Engwall KJ, Warren LC, Xia D, Qiu X. Nat Struct Mol Biol 14 413-419 (2007)
  2. The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Henrich S, Cameron A, Bourenkov GP, Kiefersauer R, Huber R, Lindberg I, Bode W, Than ME. Nat Struct Biol 10 520-526 (2003)
  3. Molecular identification of a malaria merozoite surface sheddase. Harris PK, Yeoh S, Dluzewski AR, O'Donnell RA, Withers-Martinez C, Hackett F, Bannister LH, Mitchell GH, Blackman MJ. PLoS Pathog 1 241-251 (2005)
  4. The crystal structure of PCSK9: a regulator of plasma LDL-cholesterol. Piper DE, Jackson S, Liu Q, Romanow WG, Shetterly S, Thibault ST, Shan B, Walker NP. Structure 15 545-552 (2007)
  5. Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3. Farooqi IS, Volders K, Stanhope R, Heuschkel R, White A, Lank E, Keogh J, O'Rahilly S, Creemers JW. J Clin Endocrinol Metab 92 3369-3373 (2007)
  6. Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. Henrich S, Lindberg I, Bode W, Than ME. J Mol Biol 345 211-227 (2005)
  7. 1.2 A crystal structure of the serine carboxyl proteinase pro-kumamolisin; structure of an intact pro-subtilase. Comellas-Bigler M, Maskos K, Huber R, Oyama H, Oda K, Bode W. Structure 12 1313-1323 (2004)
  8. Synthetic peptides derived from the prosegments of proprotein convertase 1/3 and furin are potent inhibitors of both enzymes. Basak A, Lazure C. Biochem J 373 231-239 (2003)
  9. 7B2 prevents unfolding and aggregation of prohormone convertase 2. Lee SN, Lindberg I. Endocrinology 149 4116-4127 (2008)
  10. Functional Characterization of Propeptides in Plant Subtilases as Intramolecular Chaperones and Inhibitors of the Mature Protease. Meyer M, Leptihn S, Welz M, Schaller A. J Biol Chem 291 19449-19461 (2016)
  11. Functional consequences of a novel variant of PCSK1. Pickett LA, Yourshaw M, Albornoz V, Chen Z, Solorzano-Vargas RS, Nelson SF, Martín MG, Lindberg I. PLoS One 8 e55065 (2013)
  12. Identification of furin pro-region determinants involved in folding and activation. Bissonnette L, Charest G, Longpré JM, Lavigne P, Leduc R. Biochem J 379 757-763 (2004)
  13. Mutational analysis of predicted interactions between the catalytic and P domains of prohormone convertase 3 (PC3/PC1). Ueda K, Lipkind GM, Zhou A, Zhu X, Kuznetsov A, Philipson L, Gardner P, Zhang C, Steiner DF. Proc Natl Acad Sci U S A 100 5622-5627 (2003)
  14. Single amino acid substitution in the PC1/3 propeptide can induce significant modifications of its inhibitory profile toward its cognate enzyme. Rabah N, Gauthier D, Wilkes BC, Gauthier DJ, Lazure C. J Biol Chem 281 7556-7567 (2006)
  15. A novel subtilase inhibitor in plants shows structural and functional similarities to protease propeptides. Hohl M, Stintzi A, Schaller A. J Biol Chem 292 6389-6401 (2017)
  16. Conformational analyses of a partially-folded bioactive prodomain of human furin. Bhattacharjya S, Xu P, Wang P, Osborne MJ, Ni F. Biopolymers 86 329-344 (2007)
  17. Determination of Histidine pKa Values in the Propeptides of Furin and Proprotein Convertase 1/3 Using Histidine Hydrogen-Deuterium Exchange Mass Spectrometry. Elferich J, Williamson DM, David LL, Shinde U. Anal Chem 87 7909-7917 (2015)
  18. Solution NMR structure of a sheddase inhibitor prodomain from the malarial parasite Plasmodium falciparum. He Y, Chen Y, Oganesyan N, Ruan B, O'Brochta D, Bryan PN, Orban J. Proteins 80 2810-2817 (2012)
  19. Subtleties among subtilases. The structural biology of Kex2 and furin-related prohormone convertases. Brenner C. EMBO Rep 4 937-938 (2003)
  20. A malaria parasite subtilisin propeptide-like protein is a potent inhibitor of the egress protease SUB1. Tarr SJ, Withers-Martinez C, Flynn HR, Snijders AP, Masino L, Koussis K, Conway DJ, Blackman MJ. Biochem J 477 525-540 (2020)
  21. Design and characterization of a protein fold switching network. Ruan B, He Y, Chen Y, Choi EJ, Chen Y, Motabar D, Solomon T, Simmerman R, Kauffman T, Gallagher DT, Orban J, Bryan PN. Nat Commun 14 431 (2023)
  22. Genomic discovery and structural dissection of a novel type of polymorphic toxin system in gram-positive bacteria. Li H, Tan Y, Zhang D. Comput Struct Biotechnol J 20 4517-4531 (2022)


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