# Nutritional Copper Signaling and Homeostasis

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $450,923

## Abstract

Copper appeared in biology after the great oxidation event and has become an essential cofactor for all
forms of aerobic life. Its reactivity required the evolution of specific copper handling pathways involving
transporters and chaperones in every compartment in the cell. We have developed Chlamydomonas as a
reference organism for understanding copper homeostasis in eukaryotic cells, especially in the context of
deficiency and in competition with other essential metals like zinc and iron. Previously, we enumerated the
cuproproteome of Chlamydomonas, identified a key conserved copper-sensing transcription factor and
detailed the copper regulon. Now, we report the discovery and biochemical characterization of a chloroplast
inter-membrane space-localized copper chaperone, PCH1, which arises from an alternate splicing event that
is conserved over a billion years of evolution. PCH1 can transfer Cu+ with high selectivity for its cognate
transporter PAA1 in the envelope membrane, but not PAA2 in the thylakoid membrane. A second major
discovery is of the "cuprosome", a lysosome-related compartment, which can accumulate bio-available Cu+.
Cu+ was visualized by a chemical fluorescent sensor and validated by NanoSIMS, a state of the art physical
technique. We developed heavy isotope pulse-labelling methods to demonstrate that cuprosome Cu+ is
bioavailable, which has broad impact in terms of handling Cu+ hyperaccumulation sites resulting from genetic
defects in mouse and human. In ongoing work, we are pursuing functional studies of 1) peptidylglycyl a-
amidating monooxygenase, a conserved cuproenzyme in animals and humans, localized to cilia, whose
biology is not yet well understood, 2) RSEP1, a thylakoid membrane-localized protease responsible for Cu
recycling in Chlamydomonas, and 3) other components of the Cu regulon. Finally, we have used RNA-Seq
transcriptome profiling to distinguish the zinc regulon and expand the copper regulon.
During the next period, we will 1) purify the Cu+-binding ligand in the cuprosome, 2) use high throughput
genetic analyses to identify mechanisms of loading and unloading the cuprosome, 3) distinguish whether
zincosomes, cuprosomes and toxic metal sequestering sites are identical or specialized versions of the
same compartment, 4) identify additional zinc- and copper-responsive transcription factors / sensors in
Chlamydomonas via genetic screens, and 5) continue functional studies of the target genes of the copper
and zinc regulons, including especially novel "pioneer" components, as well as candidate copper
homeostasis factors involved in copper movement between compartments.

## Key facts

- **NIH application ID:** 9922315
- **Project number:** 5R37GM042143-28
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** SABEEHA MERCHANT
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,923
- **Award type:** 5
- **Project period:** 1989-06-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922315

## Citation

> US National Institutes of Health, RePORTER application 9922315, Nutritional Copper Signaling and Homeostasis (5R37GM042143-28). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9922315. Licensed CC0.

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