# Mechanisms for cellular copper import via secreted cuproproteins

> **NIH NIH R16** · TEXAS STATE UNIVERSITY · 2024 · $188,125

## Abstract

Project Summary:
Copper is an essential micronutrient and a required redox-active cofactor for enzymes necessary for eukaryotic
respiration, oxidative stress resistance, and the production of functionalized cell signaling molecules. Very
recently, Cryptococcus neoformans Bim1 was reported to represent a new class of secreted and cell surface-
associated cuproproteins that promote fungal Cu-uptake via high-affinity CTR Cu-transporters during host
colonization. Homologs to C. neoformans Bim1 are highly represented in the genome of several fungal
pathogens affecting humans, and we identify this new family of Cu-scavenging proteins as Bim1-like proteins
(BLPs). Surprisingly, there is significant sequence diversity at the BLP active site and C-terminal GPI
anchoring domain. Virtually nothing is known on how such sequence variations affect Cu-trafficking function.
Our central hypothesis is that BLP active site variation is used to modulate Cu-binding affinity and oxidation
state specificity, whereas the C-terminal domain partitions BLP proteins at the cell surface. The overall goal of
this research project is two-fold: 1. To understand how the active site diversity within the BLP family affects Cu-
binding properties. 2. To understand how BLP extracellular localization patterns alter cellular Cu-homeostasis.
We propose to use the three BLPs encoded in the opportunistic fungal pathogen Pseudogymnoascus
destructans (Pd) as prototypes for the natural diversity of this new family of extracellular Cu-scavengers. We
will test our hypothesis in the following (2) specific research aims: Aim 1. To determine the impact of BLP
active site variation.; Aim 2. To define the role of Bim1-like protein (BLP) isoforms in extracellular Cu
trafficking. Under the first aim, we will (i) develop a recombinant expression platform to produce wild type and
variant PdBLPs. We will in (ii) determine how active site variation alters the metal-binding properties and the
copper coordination environment. Finally, in (iii) we will determine how active site variation alters Cu-redox
properties. In aim 2, we define the role of BLP isoforms in extracellular Cu trafficking. We will test the
innovative hypothesis that BLPs can partition at the cell surface to relay Cu to the cell surface and boost Cu-
import efficiency. To test this hypothesis, we will leverage the power of Saccharomyces cerevisiae (Sc)
genetics to build a model of the BLP/CTR uptake pathway. In (i-ii) we will optimize the recombinant expression
of PdCTR transporters and PdBLPs in S. cerevisiae. This will involve the rigorous characterization of protein
expression and localization patterns at the plasma membrane and cell wall. In (iii) we will assess the impact of
PdBLP expression levels and extracellular localization in facilitating Cu-import from diffusible and solid
supported Cu sources. The expected outcomes of this work are a basic understanding of how this novel BLP
Cu-uptake pathway functions to ensure adequate deli...

## Key facts

- **NIH application ID:** 10846829
- **Project number:** 5R16GM146716-03
- **Recipient organization:** TEXAS STATE UNIVERSITY
- **Principal Investigator:** Ryan Loren Peterson
- **Activity code:** R16 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,125
- **Award type:** 5
- **Project period:** 2022-07-21 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846829

## Citation

> US National Institutes of Health, RePORTER application 10846829, Mechanisms for cellular copper import via secreted cuproproteins (5R16GM146716-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10846829. Licensed CC0.

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