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Structural studies of the Hsp70/Hsp90 organizing protein of Plasmodium falciparum and its modulation of Hsp70 and Hsp90 ATPase activities
Affiliation:1. Instituto de Química de São Carlos, Universidade de São Paulo, São Carlos, SP, Brazil;2. Instituto de Física, Universidade de São Paulo, São Paulo, SP, Brazil;1. SCITEC-CNR, via Mario Bianco 9, 20131 Milan, Italy;2. Department of Chemistry, University of Pavia, via Taramelli 12, 27100 Pavia, Italy;1. Department of Biological Sciences, University of North Carolina, Charlotte, North Carolina, USA;2. Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA;3. Geriatrics Center, University of Michigan, Ann Arbor, Michigan, USA;1. Biomedical Biotechnology Research Unit, Department of Biochemistry and Microbiology, Rhodes, Rhodes University, Grahamstown 6140, South Africa;2. Parasitology, Philipps University Marburg, 35043 Marburg, Germany;3. College of Health and Biomedicine, Victoria University, Melbourne 8001, VIC, Australia
Abstract:HOP is a cochaperone belonging to the foldosome, a system formed by the cytoplasmic Hsp70 and Hsp90 chaperones. HOP acts as an adapter protein capable of transferring client proteins from the first to the second molecular chaperone. HOP is a modular protein that regulates the ATPase activity of Hsp70 and Hsp90 to perform its function. To obtain more detailed information on the structure and function of this protein, we produced the recombinant HOP of Plasmodium falciparum (PfHOP). The protein was obtained in a folded form, with a high content of α-helix secondary structure. Unfolding experiments showed that PfHOP unfolds through two transitions, suggesting the presence of at least two domains with different stabilities. In addition, PfHOP primarily behaved as an elongated dimer in equilibrium with the monomer. Small-angle X-ray scattering data corroborated this interpretation and led to the reconstruction of a PfHOP ab initio model as a dimer. Finally, the PfHOP protein was able to inhibit and to stimulate the ATPase activity of the recombinant Hsp90 and Hsp70–1, respectively, of P. falciparum. Our results deepened the knowledge of the structure and function of PfHOP and further clarified its participation in the P. falciparum foldosome.
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