Structure and Function of HtrA Family Proteins, the Key Players in Protein Quality Control

Abstract

High temperature requirement A (HtrA) and its homologues constitute the HtrA familiy proteins, a group of heat shock-induced serine proteases. Bacterial HtrA proteins perform crucial functions with regard to protein quality control in the periplasmic space, functioning as both molecular chaperones and proteases. In contrast to other bacterial quality control proteins, including ClpXP, ClpAP, and HslUV, HtrA proteins contain no regulatory components or ATP binding domains. Thus, they are commonly referred to as ATP-independent chaperoneproteases. Whereas the function of ATP-dependent chaperone-proteases is regulated by ATP hydrolysis, HtrA exhibits a PDZ domain and a temperature-dependent switch mechanism, which effects the change in its function from molecular chaperone to protease. This mechanism is also related to substrate recognition and the fine control of its function. Structural and biochemical analyses of the three HtrA proteins, DegP, DegQ, and DegS, have provided us with clues as to the functional regulation of HtrA proteins, as well as their roles in protein quality control at atomic scales. The objective of this brief review is to discuss some of the recent studies which have been conducted regarding the structure and function of these HtrA proteins, and to compare their roles in the context of protein quality control.

The homotrimeric structure of HtrA2 is indispensable for executing its serine protease activity

“…Each of serine protease domains in HtrA2 is involved in mediating the formation of a pyramid-shaped homotrimer. The PDZ domains in E. coli HtrA appear to facilitate entry of the damaged or denatured proteins into the proteolytic active sites (Maurizi, 2002;Schlieker et al, 2004;Kim and Kim, 2005). In contrast, the PDZ domains in HtrA2 are hindered substrate access to the proteolytic active sites, as supported by eviThe homotrimeric structure of HtrA2 is indispensable for executing its serine protease activity dence that deletion of the PDZ domain from HtrA2 relieves inhibition and thus increasing the proteolytic activity (Martins et al, 2003;Gupta et al, 2004).…”

“…The recent crystal structures of two members of the HtrA protein family, human HtrA2 and E. coli HtrA, provide insights into their structure-function relationship (Gray et al, 2000;Li et al, 2002;Maurizi, 2002;Kim and Kim, 2005). A functional HtrA protein forms a hexamer molecule assembled by staggered association of two trimeric rings.…”

Relapsing fever spirochaetes produce a serine protease that provides resistance to oxidative stress and killing by neutrophils

“…E. coli has three genes, degP, degQ, degS, that encode proteases in the HtrA family (Lipinska et al, 1988;Waller and Sauer, 1996). These proteins also have chaperone properties implicated in protein quality control (Kim and Kim, 2005). degP expression in E. coli is co-regulated by sigma (E) and CpxAR, two of the three stress response signal transduction pathways (Raivio, 2005).…”

The mitochondrial serine protease HtrA2/Omi: an overview

“…51 Second, both HtrA2/Omi and DegS lack the extended LA loop that ensures the dimerization of two DegP homotrimers and controls the height of the large central cavity of the hexamer to prevent properly folded proteins from entering the proteolytic sites. 1,54 In marked contrast to DegP, the short LA loop found in HtrA2/ Omi and DegS does not interfere with proper formation of the active site. 1,12,53 Indeed, the relative orientation of the PDZ domain was suggested to modulate proteolytic activity in these proteases.…”