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Methods to Investigate the Regulatory Role of Small RNAs and Ribosomal Occupancy of Plasmodium falciparum
Published on: December 4, 2015
Structural and functional studies of interaction between Plasmodium falciparum knob-associated histidine-rich protein
Xinhong Pei1, Xiuli An, Xinhua Guo
1Red Cell Physiology Laboratory, New York Blood Center, New York, New York, 10021, USA.
Abstract:
Plasmodium falciparum dramatically modifies the structure and function of the membrane of the parasitized host erythrocyte. Altered membrane properties are the consequence of the interaction of a group of exported malaria proteins with host cell membrane proteins. KAHRP (the knob-associated histidine-rich protein), a member of this group, has been shown to interact with erythrocyte membrane skeletal protein spectrin. However, the molecular basis for this interaction has yet to be defined. In the present study, we defined the binding motifs in both KAHRP and spectrin and identified a functional role for this interaction. We showed that spectrin bound to a 72-amino-acid KAHRP fragment (residues 370-441). Among nine-spectrin fragments, which encompass the entire alpha and beta spectrin molecules (four alpha spectrin and five beta spectrin fragments), KAHRP bound only to one, the alpha N-5 fragment. The KAHRP-binding site within the alpha N-5 fragment was localized uniquely to repeat 4. The interaction of full-length spectrin dimer to KAHRP was inhibited by repeat 4 of alpha spectrin. Importantly, resealing of this repeat peptide into erythrocytes mislocalized KAHRP in the parasitized cells. We concluded that the interaction of KAHRP with spectrin is critical for appropriate membrane localization of KAHRP in parasitized erythrocytes. As the presence of KAHRP at the erythrocyte membrane is necessary for cytoadherence in vivo, our findings have implications for the development of new therapies for mitigating the severity of malaria infection.
Insights
Malaria parasite Plasmodium falciparum exports knob-associated histidine-rich protein (KAHRP) that binds to spectrin in host erythrocytes. This interaction is crucial for KAHRP localization and malaria cytoadherence.
Area of Science:
- Malariology
- Cell Biology
- Protein Interactions
Background:
- Plasmodium falciparum infection alters host erythrocyte membrane properties.
- Exported malaria proteins interact with host cell membrane proteins.
- Knob-associated histidine-rich protein (KAHRP) interacts with spectrin, but the molecular basis is unknown.
Purpose of the Study:
- Define the binding motifs of KAHRP and spectrin interaction.
- Identify the functional role of the KAHRP-spectrin interaction.
Main Methods:
- Used spectrin fragments to map KAHRP binding sites.
- Tested inhibition of spectrin dimer-KAHRP interaction with alpha spectrin repeat 4.
- Resealed alpha spectrin repeat 4 peptide into erythrocytes to assess KAHRP localization.
Main Results:
- Spectrin binds to a 72-amino acid KAHRP fragment (residues 370-441).
- KAHRP binds specifically to the alpha N-5 fragment of spectrin, localized to repeat 4.
- Alpha spectrin repeat 4 inhibits spectrin dimer-KAHRP interaction and mislocalizes KAHRP when resealed into erythrocytes.
Conclusions:
- The KAHRP-spectrin interaction, mediated by alpha spectrin repeat 4, is critical for KAHRP membrane localization in infected erythrocytes.
- Proper KAHRP localization is necessary for malaria parasite cytoadherence in vivo.
- Findings suggest potential therapeutic targets for malaria.
