Comparative sequence and structural analyses of neuroserpin: the serine protease inhibitor family

Abstract

Neuroserpin, a clade of serine proteinase inhibitors (serpins) is a selective inhibitor of tissue-type plasminogen activator (tPA) and usually has more than 220 residues. The crystal structure of native human neuroserpin has been reported by Sayaka et al., [17] at 2.1 Å resolution. The native fold of neuroserpin is composed of a five stranded β-sheet A and a mobile helical reactive center loop (RCL). The structure also contains an omega loop (Ω-loop), which contributes to the inhibition of tPA and a helix 'F' that plays an important role in folding, complex formation and polymerization. In this study, we identify new members of the neuroserpin family by comparative sequence analyses, and we analyze the conservation of the reactive center loop, the omega loop, the helix 'F' and other consensus residues, in the newly found relatives, which differ from the consensus sequences of other clades of serpins. By comparative structural analyses of neuroserpin with its structurally similar proteins, we reveal the structural patterns and the stabilizing interactions, that are unique among the members of neuroserpin family.