Grant Details
Description
PROJECT SUMMARY _____
Thrombospondin type-1 repeats (TSRs) are small, adhesive protein domains that are found in phyla as diverse
as chordates, nematodes, and apicomplexans. TSR-bearing proteins, which are typically localized to the cell
surface or extracellular matrix, serve a wide variety of functions, including cell attachment and motility. TSRs
are usually glycosylated at highly conserved motifs wherein tryptophans may be modified with a C-linked
mannose and a conserved serine or threonine residue may be modified with an O-linked fucose.
Parasites of the genus Plasmodium, the causative agent of the disease malaria, express ten conserved TSR-
bearing proteins at various stages throughout their life cycle. Disrupting any one of them severely disrupts or
halts parasite development. The most extensively studied of the TSR-bearing proteins are the sporozoite
surface proteins CSP and TRAP. It has been shown that the TSRs in these proteins contain motifs that bind to
proteoglycans and thus play a role in parasite invasion of host cells. We have recently used mass spectrometry
to demonstrate for the first time that the TSRs of CSP and TRAP are glycosylated in vivo. This discovery
revealed a gap in the understanding of these otherwise well-studied invasins: TSR-bearing proteins are critical
to the Plasmodium life cycle, yet nothing is known about the role of glycosylation in maintaining their function
or virulence.
We hypothesize that the O-fucosylation and C-mannosylation of TSRs in Plasmodium is required for the proper
function of the glycosylated proteins, and we predict that preventing glycosylation of these proteins will inhibit
their function and disrupt the Plasmodium life cycle. In order to test this hypothesis, we will first characterize
the glycosylation status of all TSR-bearing proteins expressed in P. falciparum. We will then generate
transgenic parasite lines with mutations that prevent modification of the TSRs of specific proteins in order to
determine the role of glycosylation in the function of these virulence factors.
Status | Active |
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Effective start/end date | 06/1/20 → 05/31/24 |
Funding
- National Institute of Allergy and Infectious Diseases: $844,019.00
- National Institute of Allergy and Infectious Diseases: $833,059.00
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