Caister Academic Press

PDZ domains as sensors of other proteins

Rebecca Kirk and Tim Clausen
from: Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition (Edited by: Stephen Spiro and Ray Dixon). Caister Academic Press, U.K. (2010)

Abstract

Proteins containing PDZ domains have been shown to mediate a wide range of protein-protein interactions and to function as molecular scaffolds in the assembly of multi-protein complexes. The most studied typical function of PDZ domains is to recognize and bind short specific sequences at the C-terminal tails of their interacting partners; however other PDZ-mediated interactions including the recognition of internal motifs have been reported. PDZ domains are frequently combined with catalytic domains like, for example, protease, kinase and phosphatase domains. In this case, the PDZ domains do not simply function as molecular glue bringing entities of signaling cascades in contact with each other, but rather exert important regulatory functions by controlling the activity of their co-working partner domain. For one class of PDZ-enzymes, the HtrA proteases, the inter-domain communication has been studied in molecular detail providing the first insight into how PDZ domains control enzyme function and sense different external stimuli. HtrA proteins function to monitor protein homeostasis in the cell. In prokaryotes this family of proteins underpins processes required for tolerance against various folding stresses and pathogenicity. Human HtrA proteins are involved in mammalian stress response pathways and in the prevention of the onset of protein misfolding diseases: including arthritis, Parkinson's and Alzheimer's disease. Recent biochemical and structural data indicate that the PDZ domains of HtrA proteins could act as sensors of folding stress, autoproteolysis, misfolded proteins, cleavage products and of specific interaction partners. As detailed in this review, interactions undergone with the PDZ domain are the starting point of an intramolecular signaling mechanism that ultimately modulates the activity of the attached catalytic domain. In this review we will focus on the function of PDZ domains as sensors for various peptide and protein signals. We will introduce PDZ domains and describe PDZ-enzymes. Of these the best understood is the family of HtrA proteases, whose structures, functions, signals and downstream cascades will be described. Finally we will discuss the recent findings illustrating how PDZ domains couple the sensing of various stimuli with the adjustment of protease function read more ...
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