Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis

Tadaaki Kishi, Masato Kato, Toshiyuki Shimizu, Keiko Kato, Kazumasa Matsumoto, Shigetaka Yoshida, Sadao Shiosaka, Toshio Hakoshima

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Neuropsin is a novel serine protease, the expression of which is highly localized in the limbic areas of the mouse brain and which is suggested to be involved in kindling epileptogenesis and hippocampal plasticity. The 2.1-A resolution crystal structure of neuropsin provides the first three- dimensional view of one of the serine proteases highly expressed in the nervous system, and reveals a serine protease fold that exhibits chimeric features between trypsin and nerve growth factor-γ (NGFγ), a member of the kallikrein family. Neuropsin possesses an N-glycosylated 'kallikrein loop' but forms six disulfide bonds corresponding to those of trypsin. The ordered kallikrein loop projects proline toward the active site to restrict smaller residues or proline at the P2 position of substrates. Loop F, which participates in forming the S3/S4 sites, is similar to trypsin rather than NGFγ. The unique conformations of loops G and H form an S1 pocket specific for both arginine and lysine. These characteristic loop structures forming the substrate-binding site suggest the novel substrate specificity of neuropsin and give a clue to the design of its specific inhibitors.

Original languageEnglish (US)
Pages (from-to)4220-4224
Number of pages5
JournalJournal of Biological Chemistry
Volume274
Issue number7
DOIs
StatePublished - Feb 12 1999

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Kallikreins
Serine Proteases
Trypsin
Peptide Hydrolases
Crystal structure
Nerve Growth Factor
Proline
Substrates
Neurology
Substrate Specificity
Disulfides
Nervous System
Lysine
Plasticity
Arginine
Conformations
Brain
Catalytic Domain
Binding Sites

ASJC Scopus subject areas

  • Biochemistry

Cite this

Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. / Kishi, Tadaaki; Kato, Masato; Shimizu, Toshiyuki; Kato, Keiko; Matsumoto, Kazumasa; Yoshida, Shigetaka; Shiosaka, Sadao; Hakoshima, Toshio.

In: Journal of Biological Chemistry, Vol. 274, No. 7, 12.02.1999, p. 4220-4224.

Research output: Contribution to journalArticle

Kishi, T, Kato, M, Shimizu, T, Kato, K, Matsumoto, K, Yoshida, S, Shiosaka, S & Hakoshima, T 1999, 'Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis', Journal of Biological Chemistry, vol. 274, no. 7, pp. 4220-4224. https://doi.org/10.1074/jbc.274.7.4220
Kishi, Tadaaki ; Kato, Masato ; Shimizu, Toshiyuki ; Kato, Keiko ; Matsumoto, Kazumasa ; Yoshida, Shigetaka ; Shiosaka, Sadao ; Hakoshima, Toshio. / Crystal structure of neuropsin, a hippocampal protease involved in kindling epileptogenesis. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 7. pp. 4220-4224.
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