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DOE OSTI · 3014067

A Trichomonas vaginalis C2-XYPPX-repeat protein with a structured C2 domain displaying dampened flexibility upon binding calcium

Buchko, Garry W. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Washington State Univ., Pullman, WA (United States)] (ORCID:0000000236391061)·Liu, Lijun [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Kansas, Lawrence, KS (United States)] (ORCID:000000030514281X)·Battaile, Kevin P. [New York Structural Biology Center (NYSBC), NY (United States)] (ORCID:0000000308333259)·Craig, Justin K. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)]·Harmon, Elizabeth K. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)] (ORCID:0000000200172705)·Van Voorhis, Wesley C. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)] (ORCID:0000000161412015)·Myler, Peter J. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Seattle Children's Research Institute (SCRI), WA (United States); Univ. of Washington, Seattle, WA (United States)]·Lovell, Scott W. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Kansas, Lawrence, KS (United States)] (ORCID:0000000232154472)
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Abstract

C2 domains are ubiquitous membrane-binding modules of ∼130 residues in eukaryotes that are often associated with proteins involved in membrane trafficking and lipid modification. The genome of Trichomonas vaginalis, the most common, non-viral, sexually transmitted human pathogen, encodes eight genes that contain a N-terminal C2 module linked to a XYPPX-repeat domain of more than four XYPPX repeats (C2-XYPPX). While the function of the XYPPX-repeat domain remains unknown, its multiple association with C2 domains in T. vaginalis suggests it is important. Here, the C2 domain from one of these C2-XYPPX-repeat proteins, Tv-C2-1, was structurally and physically characterized using X-ray crystallography and NMR spectroscopy. The crystal structure for Tv-C2-1 shows that this domain shares a fold common to all C2 domains, a compact Greek-key motif composed of eight anti-parallel β-strands in the type-2 topology. An NMR chemical shift perturbation study with Ca 2+ showed that Tv-C2-1 bound two Ca 2+ atoms primarily via two loops (loop-1 and loop-3) on the predicted calcium binding face of the protein with K d s of 58.0 ± 0.1 μM and 232 ± 6 μM. Estimations of the overall rotational correlation time, τ c , in the apo (11.1 ns) and Ca 2+ -bound (9.2 ns) state suggests the protein becomes more compact upon Ca 2+ binding, consistent with a decrease in dynamics in loop-3 and marginally in loop-1 suggested by amide 15 N heteronuclear steady-state { 1 H}- 15 N NOEs. Showing Tv-C2-1 binds calcium and adopts a compact Greek-key motif structure, two primary features of C2 domains, suggests understanding the function of the XYPPX-repeat domain may be warranted.

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NMR spectroscopyinfectious dieaseprotein X-ray crystallographyprotein dynamicssexually transmitted diseases

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Buchko, Garry W. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Pacific Northwest National Laboratory (PNNL), Richland, WA (United States); Washington State Univ., Pullman, WA (United States)] (ORCID:0000000236391061), Liu, Lijun [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Kansas, Lawrence, KS (United States)] (ORCID:000000030514281X), Battaile, Kevin P. [New York Structural Biology Center (NYSBC), NY (United States)] (ORCID:0000000308333259), Craig, Justin K. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)], Harmon, Elizabeth K. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)] (ORCID:0000000200172705), Van Voorhis, Wesley C. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Washington, Seattle, WA (United States)] (ORCID:0000000161412015), Myler, Peter J. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Seattle Children's Research Institute (SCRI), WA (United States); Univ. of Washington, Seattle, WA (United States)], Lovell, Scott W. [Seattle Structural Genomics Center for Infectious Disease (SSGCID), WA (United States); Univ. of Kansas, Lawrence, KS (United States)] (ORCID:0000000232154472). 2025-11-22. A Trichomonas vaginalis C2-XYPPX-repeat protein with a structured C2 domain displaying dampened flexibility upon binding calcium. https://doi.org/10.1016/j.biochi.2025.11.011

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