+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Identification of a pH sensor in the furin propeptide that regulates enzyme activation



Identification of a pH sensor in the furin propeptide that regulates enzyme activation



Journal of Biological Chemistry 281(23): 16108-16116



The folding and activation of furin occur through two pH- and compartment-specific autoproteolytic steps. In the endoplasmic reticulum (ER), profurin folds under the guidance of its prodomain and undergoes an autoproteolytic excision at the consensus furin site Arg-Thr-Lys-Arg107/ generating an enzymatically masked furin-propeptide complex competent for transport to late secretory compartments. In the mildly acidic environment of the trans-Golgi network/endosomal system, the bound propeptide is cleaved at the internal site 69HRGVTKR75/, unmasking active furin capable of cleaving substrates in trans. Here, by using cellular, biochemical, and modeling studies, we demonstrate that the conserved His69 is a pH sensor that regulates the compartment-specific cleavages of the propeptide. In the ER, unprotonated His69 stabilizes a solvent-accessible hydrophobic pocket necessary for autoproteolytic excision at Arg107. Profurin molecules unable to form the hydrophobic pocket, and hence, the furin-propeptide complex, are restricted to the ER by a PACS-2- and COPI-dependent mechanism. Once exposed to the acidic pH of the late secretory pathway, protonated His69 disrupts the hydrophobic pocket, resulting in exposure and cleavage of the internal cleavage site at Arg75 to unmask the enzyme. Together, our data explain the pH-regulated activation of furin and how this His-dependent regulatory mechanism is a model for other proteins.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 013139282

Download citation: RISBibTeXText

PMID: 16601116

DOI: 10.1074/jbc.M600760200


Related references

The mechanism by which a propeptide-encoded pH sensor regulates spatiotemporal activation of furin. Journal of Biological Chemistry 288(26): 19154-19165, 2013

Identification of a somatostatin-14-generating propeptide converting enzyme as a member of the kex2/furin/PC family. Endocrinology 129(4): 2263-2265, 1991

Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage. Embo Journal 16(7): 1508-1518, 1997

TGFbeta1 regulates gene expression of its own converting enzyme furin. Journal of Clinical Investigation 99(8): 1974-1983, 1997

Bone morphogenetic protein-1 processes the NH2-terminal propeptide, and a furin-like proprotein convertase processes the COOH-terminal propeptide of pro-alpha1(V) collagen. Journal of Biological Chemistry 273(42): 27511-7, 1998

Bone morphogenetic protein-1 processes the NH2-terminal propeptide, and a furin-like proprotein convertase processes the COOH-terminal propeptide of pro-a1(V) collagen. The Journal of Biological Chemistry 273(42): 511-17, 1998

Interaction of Mint3 with Furin regulates the localization of Furin in the trans-Golgi network. Journal of Cell Science 121(Pt 13): 2217-2223, 2008

Furin regulates both the activation of Pseudomonas exotoxin A and the Quantity of the toxin receptor expressed on target cells. Infection and Immunity 64(2): 524-527, 1996

Sequence of the cDNA encoding rat furin, a possible propeptide-processing endoprotease. Nucleic Acids Research 18(22): 6719-6719, 1990

Sequence of the complementary dna encoding rat furin a possible propeptide processing endoprotease. Nucleic Acids Research 18(22): 6719, 1990

Identification of furin pro-region determinants involved in folding and activation. Biochemical Journal 379(Pt 3): 757-763, 2004

Activation biosensor for G protein-coupled receptors: a FRET-based m1 muscarinic activation sensor that regulates G(q). Plos One 7(9): E45651, 2013

A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. Journal of Biological Chemistry 275(48): 37712-7, 2000

Furin Functions as a Nonproteolytic Chaperone for Matrix Metalloproteinase-28: MMP-28 Propeptide Sequence Requirement. Biochemistry Research International 2011: 630319, 2010

Endoproteolytic cleavage of its propeptide is a prerequisite for efficient transport of furin out of the endoplasmic reticulum. Journal of Biological Chemistry 270(6): 2695-2702, 1995