# Dissecting the role of ApiAP2 proteins in transcriptional regulation during Plasmodium falciparum development

> **NIH NIH R01** · PENNSYLVANIA STATE UNIVERSITY, THE · 2020 · $381,817

## Abstract

Although for many years it was thought that Plasmodium parasites, the causative agents of malaria,
were devoid of sequence-specific transcription factors, work from our lab and others has now
demonstrated that they possess a limited number of such regulatory proteins. The apicomplexan AP2
(ApiAP2) proteins, which are plant-like in their origin, are now widely considered to be the single major
family of DNA binding proteins identified in the Plasmodium genome. Our central hypothesis is that
members of the ApiAP2 protein family are the major regulators of development throughout the
complete lifecycle of the malaria parasite. ApiAP2 proteins are highly variable in size and contain
anywhere from one to three AP2 DNA binding domains. We have measured the DNA binding
specificities for all AP2 domains from Plasmodium demonstrating a broad array of DNA sequence
specificities. By determining the genome-wide occurrence of these DNA motifs, we can begin to
predict the functional roles for some ApiAP2 proteins. However, detailed mechanistic studies to
confirm these predictions have been lagging. This proposal seeks to define the functional role for a
subset of ApiAP2 proteins associated with processes critical to blood-stage development including the
regulation of red blood cell invasion, commitment to gametocytogenesis and gametocyte
differentiation and maturation. First, we will define the transcriptional regulatory network of PfAP2-G
(PF3D7_1222600), which we have demonstrated to be a master regulator of sexual stage
commitment. We will also investigate two additional ApiAP2 proteins implicated in gametocyte
development (PF3D7_1317200, PF3D7_1408200) to define their role in the regulation of gametocyte
differentiation. We next propose to characterize the role of PF3D7_1007700, which we predict to be a
regulator of red blood cell invasion. Since PF3D7_1007700 contains three AP2 DNA binding domains,
each with unique DNA binding specificity, this will allow us to dissect the contribution of individual AP2
domains to the function of this protein (and other ApiAP2 proteins by analogy). Lastly, we have
identified a new conserved domain in ApiAP2 proteins and will initiate efforts to characterize the
structure and function of this domain as well as seeking to define transactivation regions within these
proteins. To accomplish our goals, we will use a combination of established techniques, including
genetic manipulation of the parasite, biochemistry, and genome-wide approaches. Understanding the
molecular mechanisms of transcriptional regulatory processes in P. falciparum will provide critically
needed tools for studying parasite development, and also presents therapeutic targets for new
intervention strategies aimed at blocking parasite maturation. ApiAP2 proteins are strictly found in
Apicomplexan parasites and therefore are attractive candidates for new antimalarial therapies.

## Key facts

- **NIH application ID:** 9913444
- **Project number:** 5R01AI125565-05
- **Recipient organization:** PENNSYLVANIA STATE UNIVERSITY, THE
- **Principal Investigator:** Manuel Llinas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,817
- **Award type:** 5
- **Project period:** 2016-05-11 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913444

## Citation

> US National Institutes of Health, RePORTER application 9913444, Dissecting the role of ApiAP2 proteins in transcriptional regulation during Plasmodium falciparum development (5R01AI125565-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9913444. Licensed CC0.

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