Oligopeptidases in peptide processing, memory disorders and pathogen virulence.

ITQB Seminar

Title: Oligopeptidases in peptide processing, memory disorders and pathogen
virulence.

Speaker: V. Fülöp

Affiliation: School of Life Sciences, University of Warwick, U.K.

Host: Maria Arménia Carrondo Coordinator of Macromolecular Crystallography Unit

Abstract:

Prolyl oligopeptidase family enzymes regulate the activity of
biologically active peptides and peptide hormones, and they are
implicated in diseases, including amnesia, depression, diabetes, and
trypanosomiasis. Distinctively, these serine oligopeptidases hydrolyze
only relatively short peptide substrates, while large structured
peptides and proteins are not usually cleaved. Oligopeptidases have a
C-terminal alpha/beta-hydrolase catalytic domain that is similar to
lipases and esterases. An N-terminal beta-propeller domain regulates
access to the buried active site, explaining the observed oligopeptidase
activity.

We have obtained a number of structures from the family, including the
paradigm prolyl ologopeptidase. Our most recent work concentrated on
oligopeptidase B (OPB). Although the physiological role of OPB is
unknown, and its physiological substrates have not been identified, it
has a documented role in the pathogenesis of South American and African
trypanosomiasis. In Trypanosoma cruzi, the causative agent of Chagas'
disease (South American trypanosomiasis), OPB facilitates host cell
invasion by generating a calcium signaling ligand. OPB appears to be
directly involved in the virulence of the related Trypanosoma brucei,
the causative agent of African sleeping sickness. During infection, OPB
is released into the host bloodstream, where it is free to cleave
regulatory peptides present in the host serum, OPB therefore is a potent
virulence factor and therapeutic target. We recently have obtained a
crystal structure of OPB from T. brucei (paper in preparation), and the
structure revealed a novel type of enzyme activity regulation.

The catalytic and regulatory mechanisms have been investigated using a
combination of X-ray crystallography, small-angle X-ray scattering
(SAXS), site-directed mutagenesis, ion mobility mass spectrometry and
enzyme kinetic measurements to provide better understanding of the
structure–function properties of these physiologically and
pharmaceutically important enzymes.

Rea, D. and Fülöp, V. (2011). Prolyl Oligopeptidase Structure and
Dynamics. CNS & Neurological Disorders - Drug Targets. 10, 306-310.