| DATE: |
2012-04-18 10:30 - 11:30 |
| PLACE: |
#1 meeting room, 2nd floor, 4 go kan |
| TITLE: |
Structural Biology of Lysosomal Multienzymic Complex and Clinical Application for Lysosomal Storage Diseases. |
| CONTACT: |
Leonard Chavas4901 |
| SPEAKER: |
Prof. Takashi Itoh (The University of Tokushima) |
| ABSTRACT: |
Lysosomal protective protein /cathepsin A (CTSA), neuraminidase 1
(NEU1) and ¦Â-galactosidase (GLB) associate with one another to form a
multienzymic complex (1.27 MDa) to efficiently degrade glycoconjugates
and peptides in lysosomes. In addition, the interaction between NEU1 and
CTSA is essential for expression of NEU1 activity and transport of NEU1
to lysosomes. Complex formation among these enzymes is also necessary to
prevent GLB from proteolytic degradation in lysosomes. However, the
regulation mechanism underlying their biosynthesis and complex formation
are not enough elucidated.
Autosomal recessive lysosomal storage diseases (LSDs) including
galactosialidosis, sialidosis and GM1 gangliosidosis are caused by the
defects of CTSA, NEU1 and GLB genes, respectively. There is no effective
therapy for these LSDs involving neurological symptoms, although enzyme
replacement therapy (ERT), gene therapy, cell transplantation therapy,
substrate reduction therapy (SRT) are clinically available for several
other LSDs involving visceral symptoms.
Recently we have elucidated the crystal structure of the active form of
human CTSA purified from a transgenic silkworm (Tg-CTSA) overexpressing
the CTSA in the middle silk glands, and that of human GLB had been also
elucidated by Prof. T. Shimizu et al in the Univ. of Tokyo. The
structure of NEU1 has been modeled on the basis of that of NEU2 by Dr.
L.G. Chavas in KEK. Structural information of the mutant enzymes are
available to predict in silico the interaction among CTSA, NEU1 and GLB,
which is based on the missense mutations identified in the patients with
the deficiencies. However, precise structures of the multienzymic
complex should be analyzed to elucidate the molecular interaction among
them and the underlying regulation mechanism.
In this seminar, I would summarize the findings concerning the molecular
interaction among CTSA, NEU1 and GLB, and introduce the clinical
application for LSDs.
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