Chien, Peter - University of Massachusetts Amherst - Department of Biochemistry and Molecular Biology

研究领域

Protein degradation is an essential process for all biological life. Damaged or improperly folded proteins need to be cleared from the cell before they elicit toxic effects. Regulatory proteins need to be degraded so that the response they support exists only as long as it is necessary. However, as proteolysis is an irreversible event,great care must be taken to only degrade those factors as needed without disturbing the balance of other proteins. Degradation of proteins in bacteria is controlled by energy dependent proteases. These oligomeric proteases comprise unfoldase and peptidase activities encoded on separate proteins (e.g. the ClpXP and ClpAP proteases) or in separate domains within the same polypeptide (e.g., the Lon protease).The unfoldase component captures ATP hydrolysis to recognize, unfold and translocate target proteins to the peptidase compartment where the protein is hydrolyzed. Although proteases alone degrade some targets, adaptor proteins can further expand or alter substrate choice. Because these proteases have both regulatory and housekeeping roles, it is vital to understand how proteases maintain specificity while accommodating a wide range of substrates. DRIVING THE BACTERIA CELL-CYCLE WITH REGULATED PROTEIN DEGRADATION The α-proteobacterium Caulobacter crescentus undergoes an ordered series of growth and division known as the cell-cycle. As in eukaryotes, this cell-cycle is driven by waves of phosphorylation and protein degradation. This regulated degradation requires the ClpXP protease, although ClpXP levels are unchanged during the cell-cycle, indicating that it must be selectively activated. We are addressing this selective activation using purified proteins to reveal new insights into the mechanism and control of this complex process. CONTROLLING DNA REPLICATION THROUGH STRESS-RELATED PROTEASES Orderly growth requires that cells respond to environmental stress, and regulated protein degradation actively contributes to these responses. Replication of DNA is arguably the most regulated molecular event for life. We are currently exploring new ways that stress responses, proteolysis and replication converge to control cell survival.

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Kuhlmann NJ, Doxsey D, Chien P. Cargo competition for a dimerization interface restricts and stabilizes a bacterial protease adaptor. Proc Natl Acad Sci U S A. 2021 Apr 27;118(17):e2010523118. doi: 10.1073/pnas.2010523118. PMID: 33875581; PMCID: PMC8092595. Tremblay CY, Vass RH, Vachet RW, Chien P. The Cleavage Profile of Protein Substrates by ClpXP Reveals Deliberate Starts and Pauses. Biochemistry. 2020 Nov 10;59(44):4294-4301. doi: 10.1021/acs.biochem.0c00553. Epub 2020 Nov 2. PMID:33135889; PMCID: PMC7658057. Barros BB, Mahmoud SA, Chien P, Zeinert RD. Degradation of Lon in Caulobacter crescentus. J Bacteriol. 2020 Dec 7;203(1):e00344-20. doi: 10.1128/JB.00344-20. PMID: 33020222; PMCID: PMC7723953. Zeinert RD, Baniasadi H, Tu BP, Chien P. The Lon Protease Links Nucleotide Metabolism with Proteotoxic Stress. Mol Cell. 2020 Sep 3;79(5):758-767.e6. doi:10.1016/j.molcel.2020.07.011. Epub 2020 Aug 4. PMID: 32755596; PMCID: PMC7484108. Joshi A, Mahmoud SA, Kim SK, Ogdahl JL, Lee VT, Chien P, Yildiz FH. c-di-GMP inhibits LonA-dependent proteolysis of TfoY in Vibrio cholerae. PLoS Genet. 2020 Jun 26;16(6):e1008897. doi: 10.1371/journal.pgen.1008897. PMID: 32589664; PMCID: PMC7371385. Woldemeskel SA, Daitch AK, Alvarez L, Panis G, Zeinert R, Gonzalez D, Smith E, Collier J, Chien P, Cava F, Viollier PH, Goley ED. The conserved transcriptional regulator CdnL is required for metabolic homeostasis and morphogenesis in Caulobacter. PLoS Genet. 2020 Jan 21;16(1):e1008591. doi: 10.1371/journal.pgen.1008591. PMID: 31961855; PMCID: PMC6994171. Lariviere PJ, Mahone CR, Santiago-Collazo G, Howell M, Daitch AK, Zeinert R, Chien P, Brown PJB, Goley ED. (2019) An Essential Regulator of Bacterial Division Links FtsZ to Cell Wall Synthase Activation. Curr Biol. 2019 May 6;29(9):1460-1470.e4. doi: 10.1016/j.cub.2019.03.066. Liu J, Zeinert R, Francis L, Chien P. (2019) Lon recognition of the replication initiator DnaA requires a bipartite degron. Mol Microbiol. 2019 Jan;111(1):176-186. doi: 10.1111/mmi.14146. Epub 2018 Nov 8 Joshi KK, Battle CM, Chien P. (2018) The polar localization hub protein PopZ restrains adaptor dependent ClpXP proteolysis in Caulobacter crescentus. J Bacteriol. 2018 Aug 6. Mahmoud S, Chien P. (2018) Regulated Proteolysis in Bacteria. Annu Rev in Biochem. 2018. Jun 20;87:677-696. Vass RH, Nascembeni J, Chien P. (2017) The Essential Role of ClpXP in Caulobacter crescentus Requires Species Constrained Substrate Specificity. Front Mol Bio 2017 May 9;4:28. PubMed Link Joshi KK, Sutherland M, Chien P. (2017) Cargo engagement protects protease adaptors from degradation in a substrate-specific manner. J Biol Chem. 2017 May 15. pii: jbc.M117.786392. doi: 10.1074/jbc.M117.786392. PubMed Link Kuhlmann NJ, Chien P. (2017) Selective adaptor dependent protein degradation in bacteria. Curr Opin Microbiol. 2017 Apr 27;36:118-127. doi: 10.1016/j.mib.2017.03.013. Review. PubMed Link Joshi KK, Chien P. (2016) Regulated Proteolysis in Bacteria: Caulobacter. Annu Rev Genet. 2016 Nov 23;50:423-445. PubMed Link Liu J, Francis LI, Jonas K, Laub MT, Chien P. (2016) ClpAP is an auxiliary protease for DnaA degradation in Caulobacter crescentus. Mol Microbiol. 2016 Dec;102(6):1075-1085. PubMed Link Glynn SE, Chien P. (2016) Sending protein aggregates into a downward spiral. Nat Struct Mol Biol. 2016 Sep 6;23(9):769-70. Journal Link Vass RH, Zeinert RD, Chien P. Protease regulation and capacity during Caulobacter growth. Curr Opin Microbiol. 2016 Aug 17;34:75-81. PMID 27543838. PubMed Link Vass RH, Chien P. (2016) Two ways to skin a cat: ADEP antibiotics can kill bacteria through activation or inhibition of ClpP activity. Mol Microbiol. 2016 Mar 22. PubMed Link Joshi KK, Berge M, Radhakrishnan SK, Viollier PH, Chien P. (2015) An adaptor hierarchy regulates proteolysis during a bacterial cell cycle. Cell. October 8. PubMed Link Chien P. (2015) Not throwing baby out with the bathwater. Plant Cell. Oct; 27(10):2669-70. Journal Link