Carrie L. Partch

Last updated

Carrie L. Partch
Born
Carrie L. Stentz

(1973-11-30) 30 November 1973 (age 50)
Kirkland, Washington, USA
Alma mater
Scientific career
Fields Chronobiology, Biochemistry, Biophysics, Structural Biology
Institutions Oregon Health Sciences University

University of Texas Southwestern

University of California, Santa Cruz
Thesis Signal transduction mechanisms of cryptochrome (2006)
Doctoral advisor Aziz Sancar
Website https://www.partchlab.com/

Carrie L. Partch (born 30 November 1973) is an American protein biochemist and circadian biologist. Partch is currently a Professor in the Department of Chemistry and Biochemistry at the University of California, Santa Cruz. [1] [2] She is noted for her work using biochemical and biophysical techniques to study the mechanisms of circadian rhythmicity across multiple organisms. Partch applies principles of chemistry and physics to further her research in the field of biological clocks.

Contents

Academic career

In her undergraduate career at the University of Washington, [3] Partch earned her Bachelor of Science in Biochemistry with a minor in Italian. After three years as a Research Technician at Oregon Health Sciences University under Dr. Daniel Carr, [3] she went on to join the lab of Nobel Laureate Aziz Sancar at the University of North Carolina at Chapel Hill. While at UNC Chapel Hill, Partch earned her PhD in Biochemistry and Biophysics. Partch's PhD research focused on signal transduction mechanisms by cryptochrome proteins. [4] [5]

In her post-doctoral research, Partch focused on the interaction of the aryl hydrocarbon receptor nuclear translocator with its heterodimeric binding partner, the transcription factor HIF-2α, under Kevin Gardner at University of Texas Southwestern Medical Center. [6] [7] She subsequently moved this expertise into the circadian field to work with Joseph Takahashi, also at University of Texas Southwestern Medical Center, where she studied the related Basic Helix-Loop-Helix-PAS transcription factor that drives circadian rhythmicity, CLOCK:BMAL1. [8]

Partch began her career in teaching as an assistant professor (2011-2017) at UC Santa Cruz in the Department of Chemistry and Biochemistry. Partch went on to become an associate professor (2017-2019), and is now a professor (2019–present) in UC Santa Cruz's Chemistry and Biochemistry Department. [3]

Early research

Early research at Oregon Health Sciences University

Partch’s early research at Oregon Health Sciences University has a broad biochemical scope, her first publication focusing on the regulation of IL-15-stimulated TNF-alpha production, a study applicable to patients with rheumatoid arthritis. [9] Similarly, Partch’s second publication on sperm-specific proteins which interact with A-kinase anchoring proteins [10] showcases fascinating biochemical research not yet involving chronobiology.

PhD Thesis Research at UNC Chapel Hill

Following Partch's earliest research at OHSU, she began to home in on cryptochrome proteins and their signal transduction mechanisms, the focus of her PhD thesis. [11] In her thesis, Partch discusses convergence in plant and animal cryptochromes, translational repressors in biological clock feedback loops, and most notably, incorporates extensive research of biological clocks into her dissertation. Partch studied mammalian cryptochromes’ interactions with protein phosphatase 5 to investigate how inhibition of PP5 affects the activity of casein kinase I epsilon, the major clock kinase. Partch delves further into her passion for chronobiology in her thesis.

Current research

Partch's Lab currently focuses on the proteins known to circadian timekeeping, and utilizes a range of structural and biophysical techniques in order to characterize the biological role of these proteins including NMR spectroscopy and X-ray crystallography. [3] Current projects include both mammalian and cyanobacterial timekeeping mechanisms. Notably, the lab recently published work in the journal Science, elucidating the role of the protein SasA in the cooperative binding of KaiB to the KaiC hexamer in the cyanobacteria l circadian clock. [12] In 2020, the lab published a paper describing how the mammalian circadian protein PERIOD and its cognate kinase Casein Kinase 1 form a molecular switch to regulate PERIOD protein stability, and therefore circadian periodicity. [13]

Role of SasA protein in cyanobacteria

Previously, many models of cyanobacterial time keeping were based solely on the continuous phosphorylation of the Kai proteins (KaiA, KaiB, and KaiC) with SasA and CikA providing only input-output signaling. These earlier dependent models relied solely on KaiC acting as the main component of the circadian oscillator with KaiA being used to phosphorylase Threonine and Serine and KaiB being used for their subsequent dephosphorylation. [14] For these reactions to work, ATP is broken down to ADP to provide the necessary energy and phosphate groups necessary to power these reactions. Partch challenged this assumption by modeling the effect of SasA proteins in differing concentrations of KaiA, KaiB, and KaiC. It was found that SasA uses structural mimicry to help fold-switched KaiB bind to the KaiC hexamer so that the nighttime repressive complex can be formed. [15] This maintains the rhythmicity of the circadian oscillator during limiting concentrations of KaiB by allowing both of the hexamers to auto phosphorylate and dephosphorylate threonine and serine. Conversely, SasA proteins compete with KaiB proteins for the binding of the KaiC hexamer when the concentration of SasA exceeds that of KaiB. The competition between these proteins can be mitigated when the concentration of SasA is less than or equal to half of the concentration of KaiB. Lower concentrations of SasA allow for KaiB to bind to the KaiC hexamer solely; it does not need to compete for KaiC binding spots with SasA.

PERIOD proteins and CK1

Carrie Partch has made significant discoveries pertaining to PERIOD protein's role in regulating the circadian clock. PERIOD proteins, Per1 and Per2, create large, multimeric complexes with the circadian repressors CRY1 and CRY2. These complexes directly bind to and inhibit the core circadian transcription factor, CLOCK:BMAL1. [16] As PERIOD proteins are central components of our biological clock, the regulation of PER1 and PER2's expression, modification, and protein stability is especially important. Additionally, casein Kinase 1 (CK1) phosphorylates both the Degron region (initiates PER degradation) and the FASP region (antagonistically stabilizes PER). [17] Partch discovered and characterized the activity of CK1 on its biological substrate in vivo. Particularly, her findings demonstrated that the CK1 tau mutation, which reduces the oscillation cycle to roughly 20 hours, amplifies the Degron activity of CK1 while diminishing the FASP activity. Additionally, she identified the molecular switch involving an anion binding site in CK1 that regulates the phosphorylation of functionally antagonistic sites in PERIOD proteins. Her research showed that mutations in period-altering kinases differentially regulate the activation loop switch to produce expected variations in PER2 stability, laying the groundwork for comprehending and controlling CK1's impact on circadian rhythms. [10]

Phosphoswitch Model

Previous research has been completed to identify key components of Familial Advanced Sleep Phase Syndrome (FASPS) also known as Advanced sleep phase disorder. [18] [19] However, Partch contributed to the development of the formalized phosphoswitch model, compiling the previous research into a single model. The phosphoswitch model is a proposed regulatory mechanism for the stabilization and destabilization of the PERIOD protein in the mammalian circadian clock. This model explains the circadian sensitivity and phenotypic differences caused by mutations within the PER2 protein at site 662 and site 478. A downstream mutation from a serine to a glycine at site 662 leads to a shorter period, underphosphorylation, and PER2 destabilization. Because of the resulting shorter period, the phosphoswitch model is a possible mechanism for Familial Advanced Sleep Phase Syndrome (FASPS). The exact role of phosphorylation within the FASP region in the stabilization of PER2 is not yet known. [20]

Awards

Related Research Articles

Advanced Sleep Phase Disorder (ASPD), also known as the advanced sleep-phase type (ASPT) of circadian rhythm sleep disorder, is a condition that is characterized by a recurrent pattern of early evening sleepiness and very early morning awakening. This sleep phase advancement can interfere with daily social and work schedules, and results in shortened sleep duration and excessive daytime sleepiness. The timing of sleep and melatonin levels are regulated by the body's central circadian clock, which is located in the suprachiasmatic nucleus in the hypothalamus.

A circadian clock, or circadian oscillator, also known as one’s internal alarm clock is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

The Casein kinase 1 family of protein kinases are serine/threonine-selective enzymes that function as regulators of signal transduction pathways in most eukaryotic cell types. CK1 isoforms are involved in Wnt signaling, circadian rhythms, nucleo-cytoplasmic shuttling of transcription factors, DNA repair, and DNA transcription.

<span class="mw-page-title-main">CLOCK</span> Human protein and coding gene

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER2</span> Protein-coding gene in the species Homo sapiens

PER2 is a protein in mammals encoded by the PER2 gene. PER2 is noted for its major role in circadian rhythms.

<span class="mw-page-title-main">FBXL3</span> Protein-coding gene in the species Homo sapiens

FBXL3 is a gene in humans and mice that encodes the F-box/LRR-repeat protein 3 (FBXL3). FBXL3 is a member of the F-box protein family, which constitutes one of the four subunits in the SCF ubiquitin ligase complex.

<span class="mw-page-title-main">CSNK1D</span> Protein-coding gene in the species Homo sapiens

Casein kinase I isoform delta also known as CKI-delta or CK1δ is an enzyme that in humans is encoded by the gene CSNK1D, which is located on chromosome 17 (17q25.3). It is a member of the CK1 family of serine/threonine specific eukaryotic protein kinases encompassing seven distinct isoforms as well as various post-transcriptionally processed splice variants in mammalians. Meanwhile, CK1δ homologous proteins have been isolated from organisms like yeast, basidiomycetes, plants, algae, and protozoa.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

<span class="mw-page-title-main">Basic helix-loop-helix ARNT-like protein 1</span> Human protein and coding gene

Basic helix-loop-helix ARNT-like protein 1 or aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL), or brain and muscle ARNT-like 1 is a protein that in humans is encoded by the BMAL1 gene on chromosome 11, region p15.3. It's also known as MOP3, and, less commonly, bHLHe5, BMAL, BMAL1C, JAP3, PASD3, and TIC.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Joseph S. Takahashi is a Japanese American neurobiologist and geneticist. Takahashi is a professor at University of Texas Southwestern Medical Center as well as an investigator at the Howard Hughes Medical Institute. Takahashi's research group discovered the genetic basis for the mammalian circadian clock in 1994 and identified the Clock gene in 1997. Takahashi was elected to the National Academy of Sciences in 2003.

Doubletime (DBT), also known as discs overgrown (DCO), is a gene that encodes the double-time protein in fruit flies. Michael Young and his team at Rockefeller University Rockefeller University first identified and characterized the gene in 1998.

<span class="mw-page-title-main">Casein kinase 1 isoform epsilon</span> Protein and coding gene in humans

Casein kinase I isoform epsilon or CK1ε, is an enzyme that is encoded by the CSNK1E gene in humans. It is the mammalian homolog of doubletime. CK1ε is a serine/threonine protein kinase and is very highly conserved; therefore, this kinase is very similar to other members of the casein kinase 1 family, of which there are seven mammalian isoforms. CK1ε is most similar to CK1δ in structure and function as the two enzymes maintain a high sequence similarity on their regulatory C-terminal and catalytic domains. This gene is a major component of the mammalian oscillator which controls cellular circadian rhythms. CK1ε has also been implicated in modulating various human health issues such as cancer, neurodegenerative diseases, and diabetes.

KaiB is a gene located in the highly-conserved kaiABC gene cluster of various cyanobacterial species. Along with KaiA and KaiC, KaiB plays a central role in operation of the cyanobacterial circadian clock. Discovery of the Kai genes marked the first-ever identification of a circadian oscillator in a prokaryotic species. Moreover, characterization of the cyanobacterial clock demonstrated the existence of transcription-independent, post-translational mechanisms of rhythm generation, challenging the universality of the transcription-translation feedback loop model of circadian rhythmicity.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Achim Kramer is a German chronobiologist and biochemist. He is the current head of Chronobiology at Charité – Universitätsmedizin Berlin in Berlin, Germany.

Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

References

  1. ↑ "UCSC Campus Directory". Archived from the original on 11 May 2021.
  2. ↑ "Carrie Partch". scholar.google.com. Retrieved 11 December 2021.
  3. 1 2 3 4 "Partch Lab Website". Archived from the original on 12 July 2016.
  4. ↑ Partch, Carrie L.; Clarkson, Michael W.; Özgür, Sezgin; Lee, Andrew L.; Sancar, Aziz (1 March 2005). "Role of Structural Plasticity in Signal Transduction by the Cryptochrome Blue-Light Photoreceptor". Biochemistry. 44 (10): 3795–3805. doi:10.1021/bi047545g. ISSN   0006-2960. PMID   15751956.
  5. ↑ Partch, C. L.; Shields, K. F.; Thompson, C. L.; Selby, C. P.; Sancar, A. (5 July 2006). "Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5". Proceedings of the National Academy of Sciences. 103 (27): 10467–10472. Bibcode:2006PNAS..10310467P. doi: 10.1073/pnas.0604138103 . ISSN   0027-8424. PMC   1502481 . PMID   16790549.
  6. ↑ Partch, Carrie L.; Card, Paul B.; Amezcua, Carlos A.; Gardner, Kevin H. (May 2009). "Molecular Basis of Coiled Coil Coactivator Recruitment by the Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT)". Journal of Biological Chemistry. 284 (22): 15184–15192. doi: 10.1074/jbc.M808479200 . PMC   2685699 . PMID   19324882.
  7. ↑ Partch, Carrie L.; Gardner, Kevin H. (10 May 2011). "Coactivators necessary for transcriptional output of the hypoxia inducible factor, HIF, are directly recruited by ARNT PAS-B". Proceedings of the National Academy of Sciences. 108 (19): 7739–7744. Bibcode:2011PNAS..108.7739P. doi: 10.1073/pnas.1101357108 . ISSN   0027-8424. PMC   3093465 . PMID   21512126.
  8. ↑ Huang, Nian; Chelliah, Yogarany; Shan, Yongli; Taylor, Clinton A.; Yoo, Seung-Hee; Partch, Carrie; Green, Carla B.; Zhang, Hong; Takahashi, Joseph S. (13 July 2012). "Crystal Structure of the Heterodimeric CLOCK:BMAL1 Transcriptional Activator Complex". Science. 337 (6091): 189–194. Bibcode:2012Sci...337..189H. doi:10.1126/science.1222804. ISSN   0036-8075. PMC   3694778 . PMID   22653727.
  9. ↑ Kasyapa, CS; Stentz, CL; Davey, MP; Carr, DW (1 September 1999). "Regulation of IL-15-stimulated TNF-alpha production by rolipram". Journal of Immunology. 163 (5): 2836–43. doi:10.4049/jimmunol.163.5.2836. PMID   10453029 . Retrieved 10 April 2023– via PubMed.
  10. 1 2 Carr, DW; Fujita, A; Stentz, CL; Liberty, GA; Olson, GE; Narumiya, S (18 May 2001). "Identification of sperm-specific proteins that interact with A-kinase anchoring proteins in a manner similar to the type II regulatory subunit of PKA". Journal of Biological Chemistry. 276 (20): 17332–8. doi: 10.1074/jbc.M011252200 . PMID   11278869.
  11. ↑ Partch, Carrie (2006). "Signal Transduction Mechanisms of Cryptochrome".{{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ Chavan, Archana G.; Swan, Jeffrey A.; Heisler, Joel; Sancar, Cigdem; Ernst, Dustin C.; Fang, Mingxu; Palacios, Joseph G.; Spangler, Rebecca K.; Bagshaw, Clive R.; Tripathi, Sarvind; Crosby, Priya (8 October 2021). "Reconstitution of an intact clock reveals mechanisms of circadian timekeeping". Science. 374 (6564): eabd4453. doi:10.1126/science.abd4453. ISSN   0036-8075. PMC   8686788 . PMID   34618577. S2CID   238475334.
  13. ↑ Philpott, Jonathan M; Narasimamurthy, Rajesh; Ricci, Clarisse G; Freeberg, Alfred M; Hunt, Sabrina R; Yee, Lauren E; Pelofsky, Rebecca S; Tripathi, Sarvind; Virshup, David M; Partch, Carrie L (11 February 2020). "Casein kinase 1 dynamics underlie substrate selectivity and the PER2 circadian phosphoswitch". eLife. 9: e52343. doi: 10.7554/eLife.52343 . ISSN   2050-084X. PMC   7012598 . PMID   32043967. Creative Commons by small.svg  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
  14. ↑ Snijder, J., Axmann, I.M. (2019). The Kai-Protein Clock—Keeping Track of Cyanobacteria’s Daily Life. In: Harris, J., Marles-Wright, J. (eds) Macromolecular Protein Complexes II: Structure and Function . Subcellular Biochemistry, vol 93. Springer, Cham. https://doi.org/10.1007/978-3-030-28151-9_12
  15. ↑ Chavan AG, Swan JA, Heisler J, Sancar C, Ernst DC, Fang M, Palacios JG, Spangler RK, Bagshaw CR, Tripathi S, Crosby P, Golden SS, Partch CL, LiWang A. Reconstitution of an intact clock reveals mechanisms of circadian timekeeping. Science. 2021 Oct 8;374(6564):eabd4453. doi: 10.1126/science.abd4453. Epub 2021 Oct 8. PMID 34618577; PMCID: PMC8686788.
  16. ↑ Aryal, Rajindra P.; Kwak, Pieter Bas; Tamayo, Alfred G.; Gebert, Michael; Chiu, Po-Lin; Walz, Thomas; Weitz, Charles J. (September 2017). "Macromolecular Assemblies of the Mammalian Circadian Clock". Molecular Cell. 67 (5): 770–782.e6. doi:10.1016/j.molcel.2017.07.017. ISSN   1097-2765. PMC   5679067 . PMID   28886335.
  17. ↑ Masuda, Shusaku; Narasimamurthy, Rajesh; Yoshitane, Hikari; Kim, Jae Kyoung; Fukada, Yoshitaka; Virshup, David M. (17 December 2019). "Mutation of a PER2 phosphodegron perturbs the circadian phosphoswitch". doi:10.1101/2019.12.16.876615 . Retrieved 27 April 2023.
  18. ↑ Toh, Kong L.; Jones, Christopher R.; He, Yan; Eide, Erik J.; Hinz, William A.; Virshup, David M.; Ptáček, Louis J.; Fu, Ying-Hui (9 February 2001). "An h Per2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome". Science. 291 (5506): 1040–1043. Bibcode:2001Sci...291.1040T. doi:10.1126/science.1057499. ISSN   0036-8075. PMID   11232563. S2CID   1848310.
  19. ↑ Xu, Y.; Toh, K. L.; Jones, C. R.; Shin, J. -Y.; Fu, Y. -H.; Ptáček, L. J. (12 January 2007). "Modeling of a Human Circadian Mutation Yields Insights into Clock Regulation by PER2". Cell. 128 (1): 59–70. doi:10.1016/j.cell.2006.11.043. ISSN   0092-8674. PMC   1828903 . PMID   17218255.
  20. ↑ Philpott, Jonathan M.; Torgrimson, Megan R.; Harold, Rachel L.; Partch, Carrie L. (1 June 2022). "Biochemical mechanisms of period control within the mammalian circadian clock". Seminars in Cell & Developmental Biology. Special Issue: The mammalian circadian clock by Ethan Buhr / Special Issue : Antibodies in the intracellular domain by William McEwan. 126: 71–78. doi:10.1016/j.semcdb.2021.04.012. ISSN   1084-9521. PMC   8551309 . PMID   33933351.
  21. ↑ "Prize Winners of Aschoff's Rule". www.clocktool.org. Archived from the original on 9 August 2020.
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