Degradation Mechanism of AAA+ Proteases and Regulation of Streptomyces Metabolism

Abstract

Hundreds of proteins work together in microorganisms to coordinate and control normal activity in cells. Their degradation is not only the last step in the cell's lifespan but also the starting point for its recycling. In recent years, protein degradation has been extensively studied in both eukaryotic and prokaryotic organisms. Understanding the degradation process is essential for revealing the complex regulatory network in microorganisms, as well as further artificial reconstructions and applications. This review will discuss several studies on protein quality-control family members Lon, FtsH, ClpP, the proteasome in Streptomyces, and a few classical model organisms, mainly focusing on their structure, recognition mechanisms, and metabolic influences.

Keywords: ClpP; FtsH; Lon; Streptomyces; proteasome; protein degradation; regulatory network.

Figure 1

Overview of the degradation mechanism of Lon protease and its regulation on metabolism. (A) N-terminal amino acids G91 and E226 of Lon protease from Mycobacterium smegmatis are the most important active sites. (B) The cartoon structure of Lon protease and the Cryo–EM structure of the N-terminal domain of Lon E. coli (The Cryo–EM structure was downloaded from the PDB database). The whole length of Lon contains N-terminal globular domains (NGDs), three-helix bundles (3Hs), interlocked long helices (LHs), an AAA+ domain, and a protease chamber. (C) The degradation of SulA by Lon protease depends on its C-terminal histidine. (D) Lon protease negatively regulates the production of pyoluteorin in Pseudomonas fluorescens Pf-5. The multiple copies of the lon gene in S. coelicolor cause an increase in the yield of undecylprodigiosin and actinorhodin.

Figure 2

Overview of the degradation mechanism of ClpP protease and its regulation on metabolism. (A) Cryo—EM structures and cartoon structures of ClpP protease and ClpX (Cryo—EM structures of E. coli were downloaded from PDB database). ClpP protease can degrade important regulators ClgR, Lon, and PopR in S. lividans. (B) Two alanines in the C-terminal of σ^AntA are essential for degradation by ClpP in S. albus S4. (C) ClpXP can specifically degrade SsrA-tagged proteins. (D) Overexpression of clpX can increase the production of actinorhodin in S. coelicolor. (E) The type II toxin—antitoxin (TA) system is regulated by ClpP protease in S. cattleya DSM46488 under osmotic pressure.

Figure 3

Overview of the degradation mechanism of FtsH protease and its regulation on metabolism. (A) The cartoon structure of FtsH protease and its Cryo—EM structure of the cytoplasmic domain from E. coli (The Cryo—EM structure was downloaded from PDB database). (B) Three kinds of substrates (RpoH, YfgM, and LpxC) of FtsH protease. The pink sphere represents the key amino acid in the degradation process. (B) In S. avermitilis, HspR can bind to ftsHp to inhibit FtsH and negatively regulate its development. SoxR can specifically bind to ftsHp to mediate the resistance of superoxide and nitric oxide by recognizing 18-nt binding site (5′-VSYCNVVMHNKVKDGMGB-3′). (C) FtsH negatively regulates the protein secretion in S. lividans TK24.

Figure 4

Overview of the degradation mechanism of Pup–proteasome and different types of Pup. (A) Degradation diagram of the interaction between the proteasome, Pup, Dop, PafA, and Mpa. The pink Cryo—EM structure of Dop is identified from Acidothermus cellulolyticus. The Cryo—EM structure of Pup-PafA complex is identified from Corynebacterium glutamicum. The purple area represents PafA, and the orange area represents Pup. The Cryo—EM structure of the Mpa—proteasome complex is identified from Mycobacterium tuberculosis (the Cryo—EM structures were all downloaded from the PDB database). (B) The alignment of Pup amino acid sequences between M. lepromatosis, M. tuberculosis, S. avermitilis, S. albulus, S. griseus, S. coelicolor, and S. roseosporus (amino acid sequences were downloaded from the NCBI database).