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J. Biol. Chem., Vol. 276, Issue 34, 31642-31650, August 24, 2001

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Proteolytic Activation of Respiratory Syncytial Virus Fusion Protein
CLEAVAGE AT TWO FURIN CONSENSUS SEQUENCES^*

Gert Zimmer, Linda Budz, and Georg Herrler

From the Institut für Virologie, Tierärztliche Hochschule Hannover, Bünteweg 17, D-30559 Hannover, Germany

The F (fusion) protein of the respiratory syncytial viruses is synthesized as an inactive precursor F₀ that is proteolytically processed at the multibasic sequence KKRKRR¹³⁶ into the subunits F₁ and F₂ by the cellular protease furin. This maturation process is essential for the F protein to gain fusion competence. We observed that proteolytic cleavage additionally occurs at another basic motif, RARR¹⁰⁹_, that also meets the requirements for furin recognition. Cleavage at both sites leads to the removal from the polypeptide chain of a glycosylated peptide of 27 amino acids. When the sequence RARR¹⁰⁹ was changed to NANR¹⁰⁹ or to RANN¹⁰⁹ by site-directed mutagenesis, cleavage by furin was completely prevented. Although the mutants were still processed at position Arg¹³⁶, they did not show any syncytia formation. Proteolytic cleavage of the modified motifs was achieved by treatment of transfected cells with trypsin converting the F mutants into their fusogenic forms. Our findings indicate that both furin consensus sequences have to be cleaved in order to activate the fusion protein.

This publication is dedicated to Prof. Dr. R. Rott on the occasion of his 75th birthday.

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