Solution Structure of the Pro-hormone Convertase 1 Pro-domain from Mus musculus

Tangrea, Michael A.; Bryan, Philip N.; Sari, Nese; Orban, John

doi:10.1016/s0022-2836(02)00543-0

Cited by 44 publications

(71 citation statements)

References 57 publications

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“…Overall, of the 17 mutants constructed, two (I60A-furin and H66A-furin) impaired the folding of pro-furin. Based on the solution structure of PC1's pro-region [24], these two residues would be predicted to be involved in the binding interface between the pro-region and the catalytic domain of furin. Since the I60A and H66A mutations caused rapid degradation of the protein, the pro-region's role as an intramolecular chaperone seems to be affected.…”

Section: Discussionmentioning

confidence: 99%

“…The NMR co-ordinates of the mouse PC1 pro-region [24] were used to create the human furin pro-region model. The catalytic and P domains of human furin were modelled by homology to the crystal structure of mouse furin [25].…”

Section: Homology Modelling and Sequence Alignmentmentioning

confidence: 99%

“…Residues predicted to be in the hydrophobic core of convertase pro-regions are boxed, while solvent-accessible hydrophobic residues at the putative binding interface between the proregion and catalytic domains are highlighted in grey. Figure 1(B) shows the secondary structure conservation between the proregion of prokaryotic subtilisin BNP and the pro-region of PC1, based on the crystal structure of BNP and the solution structure of PC1 [24]. The sequence similarities of the various convertases suggest that the pro-regions have similar overall topologies and structures.…”

Section: Sequence Alignment Between Convertase Pro-regionsmentioning

confidence: 99%

“…Figures 6(A) and 6(B) represent two angles of furin's proregion by analogy with the NMR model of the pro-region of PC1 [24]. Residues Trp-34 and Phe-67 are depicted in grey, Phe-54 and Tyr-65 are in yellow, and Val-36 and Asn-56 are in purple.…”

Section: Homology Modelling Of the Pro-region Of Furinmentioning

confidence: 99%

“…A recent study by Tangrea et al [24] identified conserved hydrophobic residues among the pro-regions of PCs. The recent solution structure of the pro-region of PC1 made it possible to classify specific residues into two groups, one forming a hydrophobic core within the pro-region itself and the other forming a hydrophobic patch involved in the binding interface between the pro-region and the catalytic domain of the enzyme, in a similar manner to that seen for the bacterial subtilisins.…”

Section: Introductionmentioning

confidence: 99%

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Identification of furin pro-region determinants involved in folding and activation

Bissonnette

Charest

Longpré

et al. 2004

Biochemical Journal

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The pro-region of the subtilisin-like convertase furin acts early in the biosynthetic pathway as an intramolecular chaperone to enable proper folding of the zymogen, and later on as an inhibitor to constrain the activity of the enzyme until it reaches the transGolgi network. To identify residues that are important for proregion function, we initially identified amino acids that are conserved among the pro-regions of various mammalian convertases. Site-directed mutagenesis of 17 selected amino acids within the 89-residue pro-region and biosynthetic labelling revealed that I60A-furin and H66A-furin were rapidly degraded in a proteasome-dependent manner, while W34A-furin and F67A-furin did not show any autocatalytic activation. Intriguingly, the latter mutants proteolytically cleaved pro-von Willebrand factor precursor to the mature polypeptide, suggesting that the mutations permitted proper folding, but did not allow the pro-region to exercise its role in inhibiting the enzyme. Homology modelling of furin's pro-region revealed that residues Ile-60 and His-66 might be crucial in forming the binding interface with the catalytic domain, while residues Trp-34 and Phe-67 might be involved in maintaining a hydrophobic core within the pro-region itself. These results provide structural insights into the dual role of furin's proregion.

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Section: Discussionmentioning

confidence: 99%

Section: Homology Modelling and Sequence Alignmentmentioning

confidence: 99%

Section: Sequence Alignment Between Convertase Pro-regionsmentioning

confidence: 99%

Section: Homology Modelling Of the Pro-region Of Furinmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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