Review The structural basis of mode of activation and functional diversity: A case study with HtrA family of serine proteases Nitu Singh, Raja R. Kuppili, Kakoli Bose ⇑ Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India article info Article history: Received 14 September 2011 Available online 18 October 2011 Keywords: HtrA PDZ domain Active site Protease Chaperone abstract HtrA (High temperature requirement protease A) proteins that are primarily involved in protein quality control belong to a family of serine proteases conserved from bacteria to humans. HtrAs are oligomeric proteins that share a common trimeric pyramidal architecture where each monomer comprises a serine protease domain and one or two PDZ domains. Although the overall structural integrity is well main- tained and they exhibit similar mechanism of activation, subtle conformational changes and structural plasticity especially in the flexible loop regions and domain interfaces lead to differences in their active site conformation and hence in their specificity and functions. Ó 2011 Elsevier Inc. All rights reserved. Introduction HtrA 1 proteins belong to a unique family of oligomeric serine proteases (S1, chymotrypsin family) that are conserved from pro- karyotes to humans. DegP or HtrA is the first one in the family to be identified in Escherichia coli [1] which has a dual temperature dependent chaperone-protease activity and is active in the peri- plasm of the bacterium. Later on its homologs have been identified and studied in wide spectrum of organisms that include bacteria, fungi, plants, frogs, fish and mammals [2]. HtrA proteases are well- known for their structural complexity which is reflected in their multi-tasking ability. The structure of the protease comprises a ser- ine protease domain and one or more C-terminal PDZ or protein-pro- tein interaction domains [2]. They usually form higher order oligomers extending from 100 kDa trimer (as in human HtrA2) to 24-mers of 1.2 MDa as in DegP [3–9]. The chief role of E. coli DegP is to degrade misfolded proteins in the periplasm [2]. However, fine-tuning of the structural organization leads to functional diver- sity amongst the family members although their overall structural integrity is well maintained. All the HtrA proteases share a common trimeric pyramidal architecture where each monomer comprises two or three major domains [10] and exhibit similar mechanism of activation. However, subtle conformational changes and variations lead to differences in their active site conformation and hence in their specificity and functions. For example, HtrA proteins are in- volved in a variety of biological functions and pathogenicity such as protein quality control including photosystem II, in plants and cyanobacteria [11], unfolded protein response (UPR), cell growth, apoptosis, arthritis, cancer and metabolism of amyloid precursor proteins [12–15]. Here, in this review we look into this intriguing as- pect with the focus on all HtrA proteins whose structures are cur- rently available in the literature. Representative HtrA family of serine proteases: structural and functional perspectives Given their unique structural conservation despite overall low sequence identity (Fig. 1A) and involvement in critical cellular functions, plethora of research has been carried out on HtrA family of serine proteases in the past decade leading to identification and characterization of HtrA proteins in different organisms. Several members of the HtrA family belong to the same organism although they might reside in different cellular compartments as shown in Table 1. Out of these several proteins, structures of some of them have been solved which provide an in-depth understanding of their overall domain organization (Fig. 1B), structural architecture and correlation between conformational dynamics and functional diversity. Prokaryotic HtrAs DegP: dual chaperone-protease activity E. coli DegP (also called HtrA or protease Do), a periplasmic heat shock protease, maintains protein homeostasis in the bacterial 0003-9861/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2011.10.007 ⇑ Corresponding author. Address: Bose Lab, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Tata Memorial Centre, KS-138, Sector 22, Kharghar, Navi Mumbai 410210, India. Fax: +91 22 27405080. E-mail address: kbose@actrec.gov.in (K. Bose). 1 Abbreviations used: HtrA, high temperature requirement protease A; IGF, Insulin- like growth factor; UPR, unfolded protein response. Archives of Biochemistry and Biophysics 516 (2011) 85–96 Contents lists available at SciVerse ScienceDirect Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi