FURIN Human Active Protein

This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. It encodes a type 1 membrane bound protease that is expressed in many tissues, including neuroendocrine, liver, gut, and brain. The encoded protein undergoes an initial autocatalytic processing event in the ER and then sorts to the trans-Golgi network through endosomes where a second autocatalytic event takes place and the catalytic activity is acquired. The product of this gene is one of the seven basic amino acid-specific members which cleave their substrates at single or paired basic residues. Some of its substrates include proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. It is also thought to be one of the proteases responsible for the activation of HIV envelope glycoproteins gp160 and gp140 and may play a role in tumor progression. This gene is located in close proximity to family member proprotein convertase subtilisin/kexin type 6 and upstream of the FES oncogene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

Function: Furin is likely to represent the ubiquitous endoprotease activity within constitutive secretory pathways and capable of cleavage at the RX(K/R)R consensus motif. Ref.7

Catalytic activity: Release of mature proteins from their proproteins by cleavage of -Arg-Xaa-Yaa-Arg-|-Zaa- bonds, where Xaa can be any amino acid and Yaa is Arg or Lys. Releases albumin, complement component C3 and vWF from their respective precursors.

Cofactor: Calcium.

Enzyme regulation: Could be inhibited by the not secondly cleaved propeptide.

Subunit structure: Interacts with FLNA

By similarity. Binds to PACS1 which mediates TGN localization and connection to clathrin adapters. Ref.12

Subcellular location: Golgi apparatus › trans-Golgi network membrane; Single-pass type I membrane protein. Cell membrane; Single-pass type I membrane protein. Note: Shuttles between the trans-Golgi network and the cell surface. Propeptide cleavage is a prerequisite for exit of furin molecules out of the endoplasmic reticulum (ER). A second cleavage within the propeptide occurs in the trans Golgi network (TGN), followed by the release of the propeptide and the activation of furin.

Tissue specificity: Seems to be expressed ubiquitously.

Domain: Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface. Ref.10

Post-translational modification: The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms. Ref.11

Sequence similarities: Belongs to the peptidase S8 family. Furin subfamily.Contains 1 homo B/P domain.