A 20 Residues Motif Delineates the Furin Cleavage Site and its Physical Properties May Influence Viral Fusion

Sun Tian

doi:10.4137/bci.s2049

Abstract

Furin is a proprotein convertase that proteolytically cleaves protein precursors to yield functional proteins. Efficient cleavage depends on the presence of a specific sequence motif on the substrate. Currently, the cleavage site motif is described as a four amino acid pattern: R-X-[K/R]-R⇓. However, not all furin cleavage recognition sites can be described by this pattern and not all R-X-[K/R]-R⇓ sites are cleaved by furin. Since many furin substrates are involved in the pathogenesis of viral infection and human diseases, it is important to accurately characterize the furin cleavage site motif. In this study, the furin cleavage site motif was characterized using statistical analysis. The data were interpreted within the 3D crystal structure of the furin catalytic domain. The results indicate that the furin cleavage site motif is comprised of about 20 residues, P14-P6′. Specific physical properties such as volume, charge, and hydrophilicity are required at specific positions. The furin cleavage site motif is divided into two parts: 1) one core region (8 amino acids, positions P6-P2′) packed inside the furin binding pocket; 2) two polar regions (8 amino acids, positions P7–P14; and 4 amino acids, positions P3′-P6′) located outside the furin binding pocket. The physical properties of the core region contribute to the binding strength of the furin substrate, while the polar regions provide a solvent accessible environment and facilitate the accessibility of the core region to the furin binding pocket. This furin cleavage site motif also revealed a dynamic relationship linking the evolution of physical properties in region P1′-P6′ of viral fusion peptides, furin cleavage efficacy, and viral infectivity.

Highlights

Many secreted proteins are synthesized as precursors that require proteolytic cleavage of part of the polypeptide to become fully functional
Many furin cleavage site motifs share a short four amino acids pattern: R-X-[K/R]-R↓, which is located inside the binding pocket of furin
One plausible structural model of the furin cleavage site motif comprises a short core region located inside the furin binding pocket, and two extended polar regions located outside the binding pocket that facilitate solvent accessibility

Summary

Introduction

Many secreted proteins are synthesized as precursors that require proteolytic cleavage of part of the polypeptide to become fully functional. A proprotein convertase involved in the proteolytic cleavage of many of these protein precursors, cycles between the trans-Golgi network and the cell surface.[1,2] In the secretory pathway, furin recognizes the cleavage motif on the protein precursors and cleaves the substrates, resulting in functional proteins. The known host substrates of furin cleavage include precursors of extracellular matrix proteins, extracellular proteases, receptors, and hormones. Many pathogenic proteins, such as fusion proteins on the viral envelope and secreted toxins of bacteria, require furin mediated cleavage to initiate pathological infectivity. The cleavage of these furin substrates influences the molecular pathogenesis of a wide range of human diseases, including cancer, neurological disorders, and various viral infections.[1,2,3,4] an accurate description of the furin cleavage site motif is crucial for understanding the molecular mechanism of furin cleavage-mediated viral infections and furin cleavage-associated human diseases

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Results

Conclusion