The function of the DegP (HtrA) protein: Protease versus chaperone

Chang, Zengyi

doi:10.1002/iub.1561

Cited by 33 publications

(35 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In addition to their proteolytic activity, HtrA family members have been reported to possess chaperone activity that, for example, allows them to promote refolding of the unfolded MalS protein (Spiess et al, 1999) and assembly of PSII dimers and supercomplexes (Sun et al, 2010b), or to stabilize folding intermediates of outer membrane proteins (Krojer et al, 2008). However, this chaperone activity has been challenged recently (Ge et al, 2014;Chang, 2016).…”

mentioning

confidence: 99%

The Chlamydomonas deg1c Mutant Accumulates Proteins Involved in High Light Acclimation

et al. 2019

View full text Add to dashboard Cite

Degradation of periplasmic proteins (Deg)/high temperature requirement A (HtrA) proteases are ATP-independent Ser endopeptidases that perform key aspects of protein quality control in all domains of life. Here, we characterized Chlamydomonas reinhardtii DEG1C, which together with DEG1A and DEG1B is orthologous to Arabidopsis (Arabidopsis thaliana) Deg1 in the thylakoid lumen. We show that DEG1C is localized to the stroma and the periphery of thylakoid membranes. Purified DEG1C exhibited high proteolytic activity against unfolded model substrates and its activity increased with temperature and pH. DEG1C forms monomers, trimers, and hexamers that are in dynamic equilibrium. DEG1C protein levels increased upon nitrogen, sulfur, and phosphorus starvation; under heat, oxidative, and high light stress; and when Secmediated protein translocation was impaired. DEG1C depletion was not associated with any obvious aberrant phenotypes under nonstress conditions, high light exposure, or heat stress. However, quantitative shotgun proteomics revealed differences in the abundance of 307 proteins between a deg1c knockout mutant and the wild type under nonstress conditions. Among the 115 upregulated proteins are PSII biogenesis factors, FtsH proteases, and proteins normally involved in high light responses, including the carbon dioxide concentrating mechanism, photorespiration, antioxidant defense, and photoprotection. We propose that the lack of DEG1C activity leads to a physiological state of the cells resembling that induced by high light intensities and therefore triggers high light protection responses.

show abstract

mentioning

confidence: 99%

The Chlamydomonas deg1c Mutant Accumulates Proteins Involved in High Light Acclimation

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In both species, the activity of DegP2 (PfDegP) could be linked to decreased free heme concentrations. Deg-family proteins play roles in the folding, maintenance, and turnover of integral membrane proteins, such as those involved in the electron transport chain [81][82][83] . PfDegP complements its ortholog in E. coli, implying functional conservation 84 .…”

Section: Discussionmentioning

confidence: 99%

Genetic screens reveal a central role for heme biosynthesis in artemisinin susceptibility

Harding

Sidik

Petrova

et al. 2019

Preprint

View full text Add to dashboard Cite

Artemisinins have revolutionized the treatment of Plasmodium falciparum malaria, however, resistance threatens to undermine global control efforts. To explore artemisinin resistance in apicomplexan parasites broadly, we used genome-scale CRISPR screens recently developed for Toxoplasma gondii to discover sensitizing and desensitizing mutations. Using a sublethal concentration of dihydroartemisinin (DHA), we uncovered the putative porphyrin transporter Tmem14c whose disruption increases DHA susceptibility. Screens performed under high doses of DHA provided evidence that mitochondrial metabolism can modulate resistance. We show that disruption of a top candidate from the screens, the mitochondrial protease DegP2, lowered levels of free heme and decreased DHA susceptibility, without significantly altering fitness in culture. Deletion of the homologous gene in P. falciparum, PfDegP, similarly lowered heme levels and DHA susceptibility. These results expose the vulnerability of the heme biosynthetic pathway for genetic perturbations that can lead to survival in the presence of DHA. We go on to show that chemically reducing heme biosynthesis can decrease the sensitivity of both T. gondii and P. falciparum to DHA, suggesting guidelines for developing combination therapies.

show abstract

“…3c and 3d) via both side-chain and main-chain atoms. In other HtrAs, the central core of the trimeric assembly was also formed by well conserved hydrophobic as well as polar interactions (de Regt et al, 2015;Wilken et al, 2004;Chang, 2016;Krojer et al, 2002;Bai et al, 2011). Taken together, it appears that mHtrA1 S387A forms a trimer primarily by hydrogen-bond, salt-bridge and hydrophobic interactions occurring in the central core of the PD in addition to intersubunit PD-PDZ* domain interactions.…”

Section: Mhtra1 S387a Exists As a Trimermentioning

confidence: 94%

“…The HtrAs have been extensively studied biochemically as well as structurally in bacteria such as Escherichia coli (Bai et al, 2011;Malet et al, 2012;Chang, 2016), Legionella fallonii (Schubert et al, 2015) and Thermotoga maritima (Kim et al, 2003), the plant Arabidopsis thaliana (Sun et al, 2012) and humans (Eigenbrot et al, 2012). All of the HtrA proteins for which structures have been elucidated to date exhibit a common structural feature.…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features

Singh

Yadav

Kumar

et al. 2018

Acta Cryst Sect D Struct Biol

View full text Add to dashboard Cite

High-temperature requirement A (HtrA) proteins, which are members of the heat-shock-induced serine protease family, are involved in extracytoplasmic protein quality control and bacterial survival strategies under stress conditions, and are associated with the virulence of several pathogens; they are therefore major drug targets. Mycobacterium tuberculosis possesses three putative HtrAs: HtrA1 (Rv1223), HtrA2 (Rv0983) and HtrA3 (Rv0125). Each has a cytoplasmic region, a transmembrane helix and a periplasmic region. Here, the crystal structure of the periplasmic region consisting of a protease domain (PD) and a PDZ domain from an M. tuberculosis HtrA1 mutant (mHtrA1) is reported at 2.7 Å resolution. Although the mHtrA1 PD shows structural features similar to those of other HtrAs, its loops, particularly L3 and LA, display different conformations. Loop L3 communicates between the PDs of the trimer and the PDZ domains and undergoes a transition from an active to an inactive conformation, as reported for an equivalent HtrA (DegS). Loop LA, which is responsible for higher oligomer formation owing to its length (50 amino acids) in DegP, is very short in mHtrA1 (five amino acids), as in mHtrA2 (also five amino acids), and therefore lacks essential interactions for the formation of higher oligomers. Notably, a well ordered loop known as the insertion clamp in the PDZ domain interacts with the protease domain of the adjacent molecule, which possibly aids in the stabilization of a trimeric functional unit of this enzyme. The three-dimensional structure of mHtrA1 presented here will be useful in the design of enzyme-specific antituberculosis inhibitors.

show abstract

The function of the DegP (HtrA) protein: Protease versus chaperone

Cited by 33 publications

References 25 publications

The Chlamydomonas deg1c Mutant Accumulates Proteins Involved in High Light Acclimation

The Chlamydomonas deg1c Mutant Accumulates Proteins Involved in High Light Acclimation

Genetic screens reveal a central role for heme biosynthesis in artemisinin susceptibility

The crystal structure of an essential high-temperature requirement protein HtrA1 (Rv1223) from Mycobacterium tuberculosis reveals its unique features

Contact Info

Product

Resources

About